Pyrazolopyrimidine compounds and uses thereof

ABSTRACT

Disclosed are compounds of Formula (I), methods of using the compounds for inhibiting HPK1 activity and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders associated with HPK1 activity such as cancer.

FIELD OF THE INVENTION

The disclosure provides compounds as well as their compositions andmethods of use. The compounds modulate hematopoietic progenitor kinase 1(HPK1) activity and are useful in the treatment of various diseasesincluding cancer.

BACKGROUND OF THE INVENTION

Hematopoietic progenitor kinase 1 (HPK1) originally cloned fromhematopoietic progenitor cells is a member of MAP kinase kinase kinasekinases (MAP4Ks) family, which includes MAP4K1/HPK1, MAP4K2/GCK,MAP4K3/GLK, MAP4K4/HGK, MAP4K5/KHS, and MAP4K6/MINK (Hu, M. C., et al.,Genes Dev, 1996. 10(18): p. 2251-64). HPK1 is of particular interestbecause it is predominantly expressed in hematopoietic cells such as Tcells, B cells, macrophages, dendritic cells, neutrophils, and mastcells (Hu, M. C., et al., Genes Dev, 1996. 10(18): p. 2251-64; Kiefer,F., et al., EMBO J, 1996. 15(24): p. 7013-25). HPK1 kinase activity hasbeen shown to be induced upon activation of T cell receptors (TCR)(Liou, J., et al., Immunity, 2000. 12(4): p. 399-408), B cell receptors(BCR) (Liou, J., et al., Immunity, 2000. 12(4): p. 399-408),transforming growth factor receptor (TGF-βR) (Wang, W., et al., J BiolChem, 1997. 272(36): p. 22771-5; Zhou, G., et al., J Biol Chem, 1999.274(19): p. 13133-8), or G_(s)-coupled PGE₂ receptors (EP2 and EP4)(Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96). As such,HPK1 regulates diverse functions of various immune cells.

HPK1 is important in regulating the functions of various immune cellsand it has been implicated in autoimmune diseases and anti-tumorimmunity (Shui, J. W., et al., Nat Immunol, 2007. 8(1): p. 84-91; Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48). HPK1 knockout micewere more susceptible to the induction of experimental autoimmuneencephalomyelitis (EAE) (Shui, J. W., et al., Nat Immunol, 2007. 8(1):p. 84-91). Inhuman, HPK1 was downregulated in peripheral bloodmononuclear cells of psoriatic arthritis patients or T cells of systemiclupus erythematosus (SLE) patients (Batliwalla, F. M., et al., Mol Med,2005. 11(1-12): p. 21-9). Those observations suggested that attenuationof HPK1 activity may contribute to autoimmunity in patients.Furthermore, HPK1 may also control anti-tumor immunity via Tcell-dependent mechanisms. In the PGE2-producing Lewis lung carcinomatumor model, the tumors developed more slowly in HPK1 knockout mice ascompared to wild-type mice (see US 2007/0087988). In addition, it wasshown that adoptive transfer of HPK1 deficient T cells was moreeffective in controlling tumor growth and metastasis than wild-type Tcells (Alzabin, S., et al., Cancer Immunol Immunother, 2010. 59(3): p.419-29). Similarly, BMDCs from HPK1 knockout mice were more efficient tomount a T cell response to eradicate Lewis lung carcinoma as compared towild-type BMDCs (Alzabin, S., et al., J Immunol, 2009. 182(10): p.6187-94). These data, in conjunction with the restricted expression ofHPK1 in hematopoietic cells and lack of effect on the normal developmentof immune cells, suggest that HPK1 may be an excellent drug target forenhancing antitumor immunity. Accordingly, there is a need for newcompounds that modulate HPK1 activity.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein constituentvariables are defined herein.

The present disclosure further provides a pharmaceutical compositioncomprising a compound of the disclosure, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient.

The present disclosure further provides methods of inhibiting HPK1activity, which comprises administering to an individual a compound ofthe disclosure, or a pharmaceutically acceptable salt thereof.

The present disclosure further provides methods of treating a disease ordisorder in a patient comprising administering to the patient atherapeutically effective amount of a compound of the disclosure, or apharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION Compounds

The present disclosure provides, a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from Cy¹, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b),NR^(c)C(O)OR^(a), NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b),C(═NOR^(a))R^(b), C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b),S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 5-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 5-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, 4 or 5 substituents independently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NOR^(a1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);wherein said C₁₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or two R¹⁰ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3, ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein said CMalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NOR^(a2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);wherein said C₁₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring eachhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₇ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or two R²¹ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R^(a), R^(c), and R^(d) is independentlyselected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹⁰; or any R^(c) andR^(d) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-10 membered heterocycloalkyl groupoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

each R^(b) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkylaminosulfonyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, amino sulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkylaminosulfonyl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(a4), R^(c4) and R^(d4) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²²;

each R^(a5), R^(c5) and R^(d5) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy carbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, anddi(C₁₋₆alkyl)aminocarbonylamino;

provided that:

1) R¹ is other than NH₂;

2) R¹ is other than CH₃;

3) R¹ is other than CH₂(quinolin-6-yl);

4) R¹ is other than NHC(O)CH₂CH₂CH₃; and

5) when Cy^(A) is unsubstituted or substituted pyrazol-4-yl, then R¹ isother than pyridin-4-yl substituted by morpholine.

In some embodiments, R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(c)R^(d),NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b),S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), and S(O)₂NR^(c)R^(d); whereinsaid C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹⁰.

In certain embodiments, R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a), SR^(a), C(O)R^(b),C(O)NR^(c)R^(d), C(O)OR^(a), and NR^(c)C(O)R^(b); wherein said C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹⁰. In some embodiments,R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl and OR^(a); whereinsaid C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹⁰. For example,R¹ can be selected from Cy¹, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; whereinsaid C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹⁰. In certainembodiments, R¹ is Cy¹ or C₂₋₆ alkenyl; wherein said C₂₋₆ alkenyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹⁰. In certain embodiments, R¹ is selected from Cy¹,C(O)NR^(c)R^(d) and NR^(c)C(O)R^(b). In certain embodiments, R¹ isselected from phenyl, pyridinyl, pyrazolyl, thiazolyl, C(O)NR^(c)R^(d)and NR^(c)C(O)R^(b); wherein the phenyl, pyridinyl, pyrazolyl, andthiazolyl are each optionally substituted with 1, 2 or 3 substituentsindependently selected from R¹⁰.

In some embodiments, R¹ is not C₁₋₆ alkyl that is optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰ (e.g.,CH₃ and CH₂(quinolin-6-yl)) In certain embodiments, R¹ is notNR^(c)R^(d) (e.g., NH₂). In some embodiments, R¹ is NR^(c)C(O)R^(b) butnot including NHC(O)CH₂CH₂CH₃.

In some embodiments, R¹ is C₂₋₆ alkenyl; wherein said C₂₋₆ alkenyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹⁰. For example, R¹ can be CHCH substituted with R¹⁰, andR¹⁰ is phenyl substituted with 4-methylpiperazin-1-yl.

In some embodiments, R¹ is Cy¹.

In some embodiments, Cy¹ is selected from 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the4-10 membered heterocycloalkyl and 5-10 membered heteroaryl each has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein a ring-forming carbon atom of 5-10membered heteroaryl and 4-10 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰.

In some embodiments, Cy¹ is C₆₋₁₀ aryl or 5-10 membered heteroaryl;wherein the 5-10 membered heteroaryl has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein the N and S are optionally oxidized;wherein a ring-forming carbon atom of 5-10 membered heteroaryl isoptionally substituted by oxo to form a carbonyl group; and wherein theC₆₋₁₀ aryl and 5-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R¹⁰.

In some embodiments, Cy¹ is C₆₋₁₀ aryl optionally substituted with 1, 2,3 or 4 substituents independently selected from R¹⁰. In certainembodiments, Cy¹ is 5-10 membered heteroaryl optionally substituted with1, 2, 3 or 4 substituents independently selected from R¹⁰. For example,Cy¹ can be phenyl, pyrazolyl, pyridinyl, pyrimidinyl, thiophenyl, andpyridone; wherein the phenyl, pyrazolyl, pyridinyl, pyrimidinyl,thiophenyl, or pyridone are each optionally substituted with 1, 2 or 3substituents independently selected from R¹⁰. In some embodiments, Cy¹is phenyl optionally substituted with 1, 2 or 3 substituentsindependently selected from R¹⁰.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), S(O)R^(b1),S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),NR^(c1)C(O)R^(b1), and S(O)₂R^(b1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),and NR^(c1)C(O)R^(b1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, halo, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), NR^(c1)R^(d1), S(O)₂R^(b1), andS(O)NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, and 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene are each optionally substituted with 1,2, or 3 substituents independently selected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, halo, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), NR^(c1)R^(d1), and S(O)₂R^(b1); whereinsaid C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 4-10 membered heterocycloalkyl-C₁₋₃ alkylene are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹¹.

In some embodiments, each R¹⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene, halo, CN, OR^(a1),C(O)R^(b1), C(O)NR^(c1)R^(d1), and NR^(c1)R^(d1); wherein said C₁₋₆alkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and4-10 membered heterocycloalkyl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹¹.

In some embodiments, each R¹⁰ is 4-10 membered heterocycloalkyloptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹¹.

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3), and S(O)₂R^(b3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), NR^(c3)R^(d3), andNR^(c3)C(O)R^(b3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, 4-10 memberedheterocycloalkyl, halo, CN, OR^(a3), C(O)R^(b3), NR^(c3)R^(d3),C(O)NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3), andS(O)₂R^(b3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl, and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, 4-10 memberedheterocycloalkyl, halo, CN, C(O)R^(b3), NR^(c3)R^(d3), andNR^(c3)C(O)R^(b3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,4-10 membered heterocycloalkyl, CN, OR^(a3), C(O)R^(b3), NR^(c3)R^(d3),NR^(c3)S(O)₂R^(b3), and S(O)₂R^(b3); wherein said C₁₋₆ alkyl and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, or3 substituents independently selected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₆ alkyl,4-10 membered heterocycloalkyl, CN, C(O)R^(b3), and NR^(c3)R^(d3);wherein said C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹².

In some embodiments, each R¹¹ is independently selected from C₁₋₃ alkyl,4-10 membered heterocycloalkyl, CN, C(O)R^(b3), and NR^(c3)R^(d3);wherein said C₁₋₃ alkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹². In some embodiments, each R¹¹ is C₁₋₃ alkyloptionally substituted with 1, 2, or 3 substituents independentlyselected from R¹².

In some embodiments, each R¹² is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), orNR^(c5)C(O)R^(b5); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g).

In some embodiments, each R¹² is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, and OR^(a5). Forexample, each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and halo. In some embodiments,each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl. For example, each R¹² is C₁₋₆ alkyl. In some embodiments,each R¹² is independently OR^(a5). In some embodiments, each R¹² isindependently C₁₋₆ alky.

In some embodiments, R¹⁰ is 4-methylpiperazin-1-yl, fluoro, methyl, CN,trifluormethyl, methoxy, N,N-dimethylaminocarbonyl,(4-methylpiperazin-1-yl)methyl, 4-morpholinylmethyl, morpholinyl,piperazin-1-yl, pyrrolidin-1-yl, N, N-dimethylamine,morpholinylmethanone, N-cyclopentylaminocarbonyl,4-(cycloprop-1-yl)morpholinyl, cyanomethyl, 4-ethylpiperazin-1-yl,N-methylaminocarbonyl, cyclopropyl, pyridin-1-yl, methylamine,1-methyl-1-cyanomethyl, tetrahydro-2H-pyran-4-yl, phenyl,1-(piperazin-1-yl)ethan-1-one, 3-hydroxy-piperidin-1-yl,4-cyano-piperidin-1-yl, 3-hydroxy-pyrrolidin-1-yl, piperidin-4-yl,4-(2-methyl-2-hydroxypropyl)piperazin-1-yl,3-methyl-3(methylhydroxy)piperidin-1-yl,1-(methylsulfonyl)piperidin-4-amino, 4-(ethylhydroxy)piperazin-1-yl,4-(methylsulfonyl)piperazin-1-yl,4-((N-methyl-N-ethyl)aminocarbonyl)piperazin-1-yl, piperidin-1-yl,4-(methylcarbonyl)piperazin-1-yl, 2-cyanophenyl,1-hydroxyethane-2-amino, (methylsulfonyl)amino-methyl,azetidin-1-ylsulfonyl, difluoromethoxy, 2-(methoxymethyl)morpholin-4-yl,4-methyl-4-hydroxypiperidin-1-yl, or 4-(2-methoxyethyl)piperazin-1-yl.

Examples of R¹⁰ can include 4-methylpiperazin-1-yl, fluoro, methyl, CN,trifluormethyl, methoxy, N,N-dimethylaminocarbonyl,(4-methylpiperazin-1-yl)methyl, 4-morpholinylmethyl, morpholinyl,piperazin-1-yl, pyrrolidin-1-yl, N, N-dimethylamine,morpholinylmethanone, N-cyclopentylaminocarbonyl,4-(cycloprop-1-yl)morpholine, cyanomethyl, 4-ethylpiperazin-1-yl,N-methylaminocarbonyl, cyclopropyl, pyridin-1-yl, methylamine,1-methyl-1-cyanomethyl, tetrahydro-2H-pyran-4-yl, phenyl, and1-(piperazin-1-yl)ethan-1-one.

In some embodiments, R¹⁰ is 4-ethylpiperazin-1-yl.

In some embodiments, Cy^(A) is selected from C₆₋₁₀ aryl and 6-10membered heteroaryl; wherein the 6-10 membered heteroaryl has at leastone ring-forming carbon atom and 1 or 2 ring-forming N heteroatoms;wherein a ring-forming carbon atom of the 6-10 membered heteroaryl isoptionally substituted by oxo to form a carbonyl group; and wherein theC₆₋₁₀ aryl and 6-10 membered heteroaryl are each optionally substitutedwith 1, 2, 3 or 4 substituents independently selected from R²⁰.

In some embodiments, Cy^(A) is C₆₋₁₀ aryl. In some embodiments, Cy^(A)is 6-10 membered heteroaryl. In certain embodiments, Cy^(A) is not5-membered heteroaryl (e.g., unsubstituted or substituted pyrazol-4-yl).

In some embodiments, Cy^(A) is phenyl, pyridinyl, isoindolin-1-onyl,1,2,3,4-tetrahydroisoquinolinyl, quinolinyl, 2,3-dihydro-1H-inden-5-yl,or 1,2,3,4-tetrahydronaphthyl; wherein the phenyl, pyridinyl,isoindolin-1-onyl, 1,2,3,4-tetrahydroisoquinolinyl, quinolinyl,2,3-dihydro-1H-inden-5-yl, and 1,2,3,4-tetrahydronaphthyl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²⁰.

In some embodiments, Cy^(A) is phenyl, pyridinyl, isoindolin-1-onyl, or1,2,3,4-tetrahydroisoquinolinyl; wherein the phenyl, pyridinyl,isoindolin-1-onyl, and 1,2,3,4-tetrahydroisoquinolinyl are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²⁰.

In some embodiments, Cy^(A) is phenyl optionally substituted with 1, 2,or 3 substituents independently selected from R²⁰.

In some embodiments, Cy^(A) is phenyl; or two adjacent R²⁰ substituentson the Cy^(A) ring, taken together with the atoms to which they areattached, form a fused 5- or 6-membered heterocycloalkyl ring, or afused C₃₋₆ cycloalkyl ring; wherein the fused 5- or 6-memberedheterocycloalkyl ring each has at least one ring-forming carbon atom and1, 2 or 3 ring-forming heteroatoms independently selected from N, O, andS; wherein a ring-forming carbon atom of each fused 5- or 6-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 5- or 6-membered heterocycloalkylring and fused C₃₋₆ cycloalkyl ring are each optionally substituted with1, 2 or 3 substituents independently selected from R²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, 4-10 memberedheterocycloalkyl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹; or two adjacent R²⁰ substituents on theCy^(A) ring, taken together with the atoms to which they are attached,form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fusedC₃₋₇ cycloalkyl ring; wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein a ring-forming carbon atom of each fused 4-, 5-, 6- or7-membered heterocycloalkyl ring is optionally substituted by oxo toform a carbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C %, haloalkyl, halo, CN, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹; or two adjacent R²⁰ substituents on the Cy^(A) ring, taken togetherwith the atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring eachhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, 4-10 memberedheterocycloalkyl, halo, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2),C(O)OR^(a2), NR^(c2)R^(d2), and NR^(c2)C(O)R^(b2); wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R²¹; or twoadjacent R²⁰ substituents on the Cy^(A) ring, taken together with theatoms to which they are attached, form a fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring; and wherein thefused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused C₃₋₆cycloalkyl ring are each optionally substituted with 1 or 2 substituentsindependently selected from R²¹.

In certain embodiments, each R²⁰ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, OR^(a2),SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), andNR^(c2)C(O)R^(b2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹; or two adjacent R²⁰ substituents on theCy^(A) ring, taken together with the atoms to which they are attached,form a fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fusedC₃₋₇ cyclo alkyl ring.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, 4-10 membered heterocycloalkyl, halo, OR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), and NR^(c2)C(O)R^(b2); or two adjacentR²⁰ substituents on the Cy^(A) ring, taken together with the atoms towhich they are attached, form a fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring or a fused C₃₋₇ cycloalkyl ring; and wherein thefused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused C₃₋₆cycloalkyl ring are each optionally substituted with 1 or 2 substituentsindependently selected from R²¹.

In certain embodiments, each R²⁰ is independently selected from C₁₋₆alkyl, halo, OR^(a2), C(O)R^(b2), and C(O)NR^(c2)R^(d2); or two adjacentR²⁰ substituents on the Cy^(A) ring, taken together with the atoms towhich they are attached, form a fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring.

In some embodiments, R²⁰ is fluoro, methyl, methoxy, chloro,(morpholino)methanone, N-methylaminocarbonyl, aminocarbonyl,(methylamino)methyl, trifluoromethyl, pyrrolidin-2-yl, piperidin-2-yl,((pyrrolidin-1-yl)methyl)carbonylamino,((N,N-dimethylamino)methyl)carbonylamino, C(O)H, 1-(methylamino)-ethyl,(ethylamino)methyl, cyanomethyl, N-methylamino, or amino; or twoadjacent R²⁰ substituents on the Cy^(A) ring, taken together with theatoms to which they are attached, form a fused piperidinyl ring. Forexample, R²⁰ is fluoro, methyl, methoxy, chloro, (morpholino)methanone,N-methylaminocarbonyl, or aminocarbonyl; or two adjacent R²⁰substituents on the Cy^(A) ring, taken together with the atoms to whichthey are attached, form a fused piperidinyl ring.

In some embodiments, each R²⁰ is independently selected from C₁₋₆ alkyl,C₁₋₆ haloalkyl, or halo; wherein said C₁₋₆ alkyl is optionallysubstituted with 1 or 2 substituents independently selected from R²¹. Insome embodiments, R²⁰ is halo (e.g., fluoro). In some embodiments, R²⁰is C₁₋₆ haloalkyl (e.g., trifluoromethyl). In some embodiments, C₁₋₆alkyl is optionally substituted with 1 substituent independentlyselected from R²¹ (e.g., R²⁰ is (methylamino)methyl). In someembodiments, R²⁰ is fluoro, trifluoromethyl or (methylamino)methyl.

In some embodiments, Cy^(A) is 2-fluoro-6-methoxyphenyl. In someembodiments, Cy^(A) is phenyl substituted with halo (e.g., fluoro), C₁₋₆haloalkyl (e.g., trifluoromethyl), and C₁₋₆ alkyl substituted with 1substituent independently selected from R²¹ (e.g., R²⁰ is(methylamino)methyl). In some embodiments, Cy^(A) is phenyl substitutedwith fluoro, trifluoromethyl, and (methylamino)methyl.

In some embodiments, provided herein is a compound having Formula(IIa1), Formula (IIa2), Formula (IIa3), Formula (IIa4) or Formula(IIa5):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; and variables Cy^(A), R¹⁰, and R¹¹ are as defined herein.

In some embodiments, one or more hydrogen atoms in a compound of thepresent disclosure can be replaced or substituted by deuterium. Forexample, the compound can be a compound of Formula (IIa1′), Formula(IIa2′), Formula (IIa3′), Formula (IIa4′) or Formula (IIa5′):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; R¹⁰, R¹¹ and Cy^(A) are as defined herein, and wherein one of morehydrogen atoms of R¹⁰, R¹¹, and Cy^(A) are optionally substituted orreplaced with one or more deuterium.

In some embodiments, provided herein is a compound having Formula(IIa1):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; and variables Cy^(A) and R¹⁰ are as defined herein.

In some embodiments, provided herein is a compound having Formula(IIa2):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; and variables Cy^(A) and R¹⁰ are as defined herein.

In some embodiments, provided herein is a compound having Formula(IIa3):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; and variables Cy^(A) and R¹⁰ are as defined herein.

In some embodiments, provided herein is a compound having Formula(IIa4):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; and variables Cy^(A) and R¹⁰ are as defined herein.

In some embodiments, provided herein is a compound having Formula(IIa5):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; and variables Cy^(A), R¹⁰, and R¹¹ are as defined herein.

In some embodiments, provided herein is a compound having Formula(IIb1):

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3,4 or 5; and variables R²⁰ and R¹ are as defined herein.

In some embodiments, provided herein is a compound having Formula(IIc1), Formula (IIc2) or Formula (IIc3):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; n is 0, 1, 2, 3, 4, or 5; and variables R¹⁰, R¹¹, and R²⁰ are asdefined herein.

In some embodiments, the compound provided herein is a compound Formula(IIc1):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; n is 0, 1, 2, 3, 4, or 5; and variables R¹⁰ and R²⁰ are as definedherein.

In some embodiments, the compound provided herein is a compound Formula(IIc2):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; n is 0, 1, 2, 3, 4, or 5; and variables R¹⁰ and R²⁰ are as definedherein.

In some embodiments, the compound provided herein is a compound Formula(IIc3):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; n is 0, 1, 2, 3, 4, or 5; and variables R¹⁰, R¹¹, and R²⁰ are asdefined herein.

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, m is 2.

In some embodiments, n is 1.

In some embodiments, n is 2.

In some embodiments, n is 3.

The disclosure also provided herein a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a),NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NOR^(a))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 6-10 membered heteroaryl; whereinthe 6-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 6-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 6-10 membered heteroaryl are each optionally substituted with 1, 2,3, 4 or 5 substituents independently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NOR^(a1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1), NR^(c1)S(O)₂NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);wherein said C₁₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or two R¹⁰ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3, ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),C(O)OR^(a3), NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3),NR^(c3)S(O)R^(b3), NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3),S(O)R^(b3), S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NOR^(a2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);wherein said C₁₋₄ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring eachhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4), C(O)OR^(a4),NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4),NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4),S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or two R²¹ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a), R^(c), and R^(d) is independently selected from H, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

or any R^(c) and R^(d) attached to the same N atom, together with the Natom to which they are attached, form a 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹⁰;

each R^(b) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl; wherein said C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹⁰;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl,C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl,C₁₋₆ alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; or any R^(c1) and R^(d1) attached tothe same N atom, together with the N atom to which they are attached,form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkylaminosulfonyl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(a4), R^(c4) and R^(d4) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²²;

each R^(a5), R^(c5) and R^(d5) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy carbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, anddi(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C %, alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 6-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1 or 2 ring-forming N heteroatoms; wherein a ring-forming carbonatom of the 6-10 membered heteroaryl is optionally substituted by oxo toform a carbonyl group; and wherein the C₆₋₁₀ aryl and 6-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or substituentsindependently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), and NR^(c3)C(O)OR^(a3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), andNR^(c5)C(O)OR^(a5);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring eachhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), andNR^(c4)C(O)OR^(a4);

each R^(a), R^(c), and R^(d) is independently selected from H, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

each R^(b) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl; wherein said C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹⁰;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a4), R^(c4) and R^(d4) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a5), R^(c5) and R^(d5) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆haloalkyl; and

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl.

In some embodiments:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), andNR^(c)C(O)R^(b); wherein said C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 6-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1 or 2 ring-forming N heteroatoms; wherein a ring-forming carbonatom of the 6-10 membered heteroaryl is optionally substituted by oxo toform a carbonyl group; and wherein the C₆₋₁₀ aryl and 6-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or substituentsindependently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),NR^(c1)R^(d1), and NR^(c1)C(O)R^(b1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), andNR^(c3)C(O)R^(b3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and halo;

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), and NR^(c2)C(O)R^(b2);

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring eachhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and halo;

each R^(a), R^(c), and R^(d) is independently selected from H, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and 4-10 membered heterocycloalkyl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; and

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl.

In some embodiments:

R¹ is selected from Cy¹ and C₂₋₆ alkenyl; wherein said C₂₋₆ alkenyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 6-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1 or 2 ring-forming N heteroatoms; wherein a ring-forming carbonatom of the 6-10 membered heteroaryl is optionally substituted by oxo toform a carbonyl group; and wherein the C₆₋₁₀ aryl and 6-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or substituentsindependently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl-C₁₋₃ alkylene, halo, CN, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), and NR^(c1)R^(d1); wherein said C₁₄ alkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 4-10membered heterocycloalkyl-C₁₋₃ alkylene are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, 4-10 memberedheterocycloalkyl, CN, C(O)R^(b3), and NR^(c3)R^(d3); wherein said C₁₋₆alkyl and 4-10 membered heterocycloalkyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹²;

each R¹² is independently C₁₋₆ alkyl;

each R²⁰ is independently selected from C₁₋₆ alkyl, halo, OR^(a2),C(O)R^(b2), and C(O)NR^(c2)R^(d2);

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring; wherein the fused 4-, 5-, 6- or7-membered heterocycloalkyl ring each has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein a ring-forming carbon atom of eachfused 4-, 5-, 6- or 7-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently C₃₋₁₀ cycloalkyl or 4-10 memberedheterocycloalkyl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H and C₁₋₆alkyl;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group;

each R^(b2) is independently 4-10 membered heterocycloalkyl;

each R^(c3) and R^(d3) is H; and

each R^(b3) is C₁₋₆ alkyl.

In some embodiments, provided herein is a compound of Formula (I), or apharmaceutically acceptable salt thereof, wherein:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, NO₂, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a),NR^(c)C(O)NR^(c)R^(d), C(═NR^(e))R^(b), C(═NOR^(a))R^(b),C(═NR^(e))NR^(c)R^(d), NR^(c)C(═NR^(e))NR^(c)R^(d), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), NR^(c)S(O)₂NR^(c)R^(d), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

Cy¹ is selected from C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 4-10 memberedheterocycloalkyl and 5-10 membered heteroaryl each has at least onering-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein the N and S areoptionally oxidized; wherein a ring-forming carbon atom of 5-10 memberedheteroaryl and 4-10 membered heterocycloalkyl is optionally substitutedby oxo to form a carbonyl group; and wherein the C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 6-10 membered heteroaryl; whereinthe 6-10 membered heteroaryl has at least one ring-forming carbon atomand 1, 2, 3, or 4 ring-forming heteroatoms independently selected fromN, O, and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of the 6-10 membered heteroaryl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₆₋₁₀ aryland 6-10 membered heteroaryl are each optionally substituted with 1, 2,3, 4 or 5 substituents independently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),OC(O)R^(b1), OC(O)NR^(c1)R^(d1), NR^(c1)R^(d1), NR^(c1)C(O)R^(b1),NR^(c1)C(O)OR^(a1), NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1),C(═NOR^(a1))R^(b1), C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)₂R^(b1),NR^(c1)S(O)₂NR^(c1)R^(d1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1),and S(O)₂NR^(c1)R^(d1); wherein said C %, alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

or two R¹⁰ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3, ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a5), SR^(a5),C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5),NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2),NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2), C(═NOR^(a2))R^(b2),C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), NR^(c2)S(O)₂NR^(c2)R^(d2),S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2);wherein said C %, alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring eachhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4), C(O)NR^(c4)R^(d4),C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), NR^(c4)C(O)OR^(a4),NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4), NR^(c4)S(O)₂NR^(c4)R^(d4),S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4), and S(O)₂NR^(c4)R^(d4);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or two R²¹ substituents taken together with the carbon atom to whichthey are attached form a spiro 3-7-membered heterocycloalkyl ring, or aspiro C₃₋₆ cycloalkyl ring; wherein each spiro 3-7-memberedheterocycloalkyl ring has at least one ring-forming carbon atom and 1, 2or 3 ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R²²;

each R²² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl, 4-7 membered heterocycloalkyl, halo, CN, OR^(a6), SR^(a6),C(O)R^(b6), C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6),NR^(c6)C(O)R^(b6), NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6),NR^(c6)S(O)₂R^(b6), NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6),S(O)NR^(c6)R^(d6), S(O)₂R^(b6), and S(O)₂NR^(c6)R^(d6); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g);

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

or any R^(c) and R^(d) attached to the same N atom, together with the Natom to which they are attached, form a 4-10 membered heterocycloalkylgroup optionally substituted with 1, 2, 3 or 4 substituentsindependently selected from R¹⁰;

each R^(b) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl; wherein said C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹⁰;

each R^(e) is independently selected from H, CN, C₁₋₆ alkyl,C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl,C₁₋₆ alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹;

each R^(e1) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkylaminosulfonyl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

each R^(e2) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆alkyl)aminosulfonyl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²;

or any R^(c3) and R^(d3) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R¹²;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹²;

each R^(a4), R^(c4) and R^(d4) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²;

or any R^(c4) and R^(d4) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3substituents independently selected from R²²;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl; wherein said C₁₋₆ alkylC₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 memberedheteroaryl and 4-7 membered heterocycloalkyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²²;

each R^(a5), R^(c5) and R^(d5) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g);

each R^(a6), R^(c6) and R^(d6) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R^(g);

each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyland C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R^(g); and

each R^(g) is independently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₂ alkylene, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃alkyl, C₁₋₃ alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl,cyano-C₁₋₃ alkyl, H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆alkyl)amino, thio, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl,carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy carbonyl, C₁₋₆alkylcarbonylamino, C₁₋₆ alkylsulfonylamino, aminosulfonyl, C₁₋₆alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl, aminosulfonylamino,C₁₋₆ alkylaminosulfonyl amino, di(C₁₋₆ alkyl)aminosulfonylamino,aminocarbonylamino, C₁₋₆ alkylaminocarbonylamino, anddi(C₁₋₆alkyl)aminocarbonylamino.

In some embodiments, wherein:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a),OC(O)R^(b), OC(O)NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a),NR^(c)S(O)R^(b), NR^(c)S(O)₂R^(b), S(O)R^(b), S(O)NR^(c)R^(d),S(O)₂R^(b), and S(O)₂NR^(c)R^(d); wherein said C₂₄₎ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 6-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1 or 2 ring-forming N heteroatoms; wherein a ring-forming carbonatom of the 6-10 membered heteroaryl is optionally substituted by oxo toform a carbonyl group; and wherein the C₆₋₁₀ aryl and 6-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or substituentsindependently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), and NR^(c3)C(O)OR^(a3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, OR^(a5), SR^(a5), C(O)R^(b5),C(O)NR^(c5)R^(d5), C(O)OR^(a5), NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), andNR^(c5)C(O)OR^(a5);

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2), OC(O)NR^(c2)R^(d2),NR^(c2)R^(d2), NR^(c2)C(O)R^(b2), NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2),NR^(c2)S(O)₂R^(b2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2), andS(O)₂NR^(c2)R^(d2); wherein said CM alkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring eachhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4), andNR^(c4)C(O)OR^(a4);

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰;

each R^(b) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl, and 5-10 membered heteroaryl; wherein said C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl are each optionally substituted with 1, 2,3, or 4 substituents independently selected from R¹⁰;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a4), R^(c4) and R^(d4) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b4) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(a5), R^(c5) and R^(d5) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆haloalkyl; and

each R^(b5) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₁₋₆ haloalkyl.

In some embodiments, wherein:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), andNR^(c)C(O)R^(b); wherein said C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 6-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1 or 2 ring-forming N heteroatoms; wherein a ring-forming carbonatom of the 6-10 membered heteroaryl is optionally substituted by oxo toform a carbonyl group; and wherein the C₆₋₁₀ aryl and 6-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or substituentsindependently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1), NR^(c1)R^(d1),and NR^(c1)C(O)R^(b1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), andNR^(c3)C(O)R^(b3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and halo;

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), and NR^(c2)C(O)R^(b2);

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring eachhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and halo;

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰

each R^(b) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆haloalkyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆haloalkyl;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and 4-10 membered heterocycloalkyl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; and

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl.

In some embodiments:

R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), andNR^(c)C(O)R^(b); wherein said C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 6-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1 or 2 ring-forming N heteroatoms; wherein a ring-forming carbonatom of the 6-10 membered heteroaryl is optionally substituted by oxo toform a carbonyl group; and wherein the C₆₋₁₀ aryl and 6-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or substituentsindependently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),NR^(c1)R^(d1), and NR^(c1)C(O)R^(b1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, halo, CN,OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3), NR^(c3)R^(d3), andNR^(c3)C(O)R^(b3); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, or 4substituents independently selected from R¹²;

each R¹² is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, and halo;

each R²⁰ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), and NR^(c2)C(O)R^(b2);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring eachhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, and NR^(c4)R^(d4);

each R^(a), R^(c), and R^(d) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹⁰

each R^(b) is independently selected from C₂₋₆ alkenyl, C₂₋₆ alkynyl,and C₁₋₆ haloalkyl;

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, and 4-10 memberedheterocycloalkyl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹;

each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, and 4-10 membered heterocycloalkyl;

each R^(a3), R^(c3) and R^(d3) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

each R^(b3) is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; and

each R^(c4) and R^(d4) is independently selected from H and C₁₋₆ alkyl.

In some embodiments:

R¹ is selected from Cy¹ and C₂₋₆ alkenyl; wherein said C₂₋₆ alkenyl isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰;

Cy¹ is selected from 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10membered heteroaryl; wherein the 4-10 membered heterocycloalkyl and 5-10membered heteroaryl each has at least one ring-forming carbon atom and1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O,and S; wherein the N and S are optionally oxidized; wherein aring-forming carbon atom of 5-10 membered heteroaryl and 4-10 memberedheterocycloalkyl is optionally substituted by oxo to form a carbonylgroup; and wherein the 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and5-10 membered heteroaryl are each optionally substituted with 1, 2, 3 or4 substituents independently selected from R¹⁰;

Cy^(A) is selected from C₆₋₁₀ aryl and 6-10 membered heteroaryl; whereinthe 5-10 membered heteroaryl has at least one ring-forming carbon atomand 1 or 2 ring-forming N heteroatoms; wherein a ring-forming carbonatom of the 6-10 membered heteroaryl is optionally substituted by oxo toform a carbonyl group; and wherein the C₆₋₁₀ aryl and 6-10 memberedheteroaryl are each optionally substituted with 1, 2, 3, or substituentsindependently selected from R²⁰;

each R¹⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 4-10membered heterocycloalkyl-C₁₋₃ alkylene, halo, CN, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), and NR^(c1)R^(d1); wherein said C₁₄ alkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 4-10membered heterocycloalkyl-C₁₋₃ alkylene are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹¹;

each R¹¹ is independently selected from C₁₋₆ alkyl, 4-10 memberedheterocycloalkyl, CN, C(O)R^(b3), and NR^(c3)R^(d3); wherein said C₁₋₆alkyl and 4-10 membered heterocycloalkyl are each optionally substitutedwith 1, 2, 3, or 4 substituents independently selected from R¹²;

each R¹² is independently C₁₋₆ alkyl;

each R²⁰ is independently selected from C₁₋₆ alkyl, C₁₋₆ haloalkyl,halo, OR^(a2), C(O)R^(b2), and C(O)NR^(c2)R^(d2); wherein said C₁₋₆alkyl is optionally substituted with 1, 2, or 3, substituentsindependently selected from R²¹;

or two adjacent R²⁰ substituents on the Cy^(A) ring, taken together withthe atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring; wherein the fused 4-, 5-, 6- or7-membered heterocycloalkyl ring each has at least one ring-formingcarbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independentlyselected from N, O, and S; wherein a ring-forming carbon atom of eachfused 4-, 5-, 6- or 7-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group;

each R²¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, and NR^(c4)R^(d4);

each R^(a1), R^(c1) and R^(d1) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl;

or any R^(c1) and R^(d1) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹¹;

each R^(b1) is independently C₃₋₁₀ cycloalkyl or 4-10 memberedheterocycloalkyl;

each R^(a2), R^(c2) and R^(d2) is independently selected from H and C₁₋₆alkyl;

or any R^(c2) and R^(d2) attached to the same N atom, together with theN atom to which they are attached, form a 4-, 5-, 6- or 7-memberedheterocycloalkyl group;

each R^(b2) is independently 4-10 membered heterocycloalkyl;

each R^(c3) and R^(d3) is H;

each R^(b3) is C₁₋₆ alkyl; and

each R^(c4) and R^(d4) is independently selected from H and C₁₋₆ alkyl.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)— includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include CM, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m) alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl: higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, ethan-1,1-diyl, propan-1,3-diyl, propan-1,2-diyl,propan-1,1-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The term “amino” refers to a group of formula —NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C═N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1} halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CH₂F, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments,the haloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, and the like. In some embodiments, arylgroups have from 6 to about 10 carbon atoms. In some embodiments arylgroups have 6 carbon atoms. In some embodiments aryl groups have 10carbon atoms. In some embodiments, the aryl group is phenyl. In someembodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-10 ring atomsincluding carbon atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridinyl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, furanyl,thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-,1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine),indolyl, isoindolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl,imidazo[1,2-d]thiazolyl, purinyl, and the like. In some embodiments, theheteroaryl group is pyridone (e.g., 2-pyridone).

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl, isoindolyl, and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur, oxygen and phosphorus, and which has4-10 ring members, 4-7 ring members, or 4-6 ring members. Includedwithin the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and7-membered heterocycloalkyl groups. Heterocycloalkyl groups can includemono- or bicyclic (e.g., having two fused or bridged rings) orspirocyclic ring systems. In some embodiments, the heterocycloalkylgroup is a monocyclic group having 1, 2 or 3 heteroatoms independentlyselected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms andheteroatoms of a heterocycloalkyl group can be optionally oxidized toform an oxo or sulfido group or other oxidized linkage (e.g., C(O),S(O), C(S) or S(O)₂, A-oxide etc.) or a nitrogen atom can bequaternized. The heterocycloalkyl group can be attached through aring-forming carbon atom or a ring-forming heteroatom. In someembodiments, the heterocycloalkyl group contains 0 to 3 double bonds. Insome embodiments, the heterocycloalkyl group contains 0 to 2 doublebonds. Also included in the definition of heterocycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the heterocycloalkyl ring, e.g., benzo or thienylderivatives of piperidine, morpholine, azepine, etc. A heterocycloalkylgroup containing a fused aromatic ring can be attached through anyring-forming atom including a ring-forming atom of the fused aromaticring. Examples of heterocycloalkyl groups include azetidinyl, azepanyl,dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino,3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl,piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-1H-inden-5-yl, isoindolinyl,tropanyl, and thiomorpholino.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereo centers). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as β-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethyl amine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium. One ormore constituent atoms of the compounds of the invention can be replacedor substituted with isotopes of the atoms in natural or non-naturalabundance. In some embodiments, the compound includes at least onedeuterium atom. For example, one or more hydrogen atoms in a compound ofthe present disclosure can be replaced or substituted by deuterium. Insome embodiments, the compound includes two or more deuterium atoms. Insome embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11 or 12 deuterium atoms. Synthetic methods for including isotopes intoorganic compounds are known in the art (Deuterium Labeling in OrganicChemistry by Alan F. Thomas (New York, N.Y., Appleton-Century-Crofts,1971; The Renaissance of H/D Exchange by Jens Atzrodt, Volker Derdau,Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007,7744-7765). Isotopically labeled compounds can used in various studiessuch as NMR spectroscopy, metabolism experiments, and/or assays.

Substitution with heavier isotopes such as deuterium, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. (A. Kerekes et. al. J.Med. Chem. 2011, 54, 201-210; R. Xu et. al. J. Label Compd. Radiopharm.2015, 58, 308-312).

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of Formula (I) can be prepared, e.g., using a process asillustrated in the schemes below.

Compounds of Formula (I) with a variety of substitution at position R¹such as those described herein can be prepared, using a process asillustrated in Scheme 1. In the process depicted in Scheme 1, compoundsof Formula 1-2 is formed after protection of the NH group of thepyrazole ring of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine 1-1 with asuitable protecting group (e.g. SEM or Boc). The chloro substituent inthe compounds of Formula 1-2 can be converted into Cy^(A) via a numberof different cross-coupling reactions, including Suzuki (e.g., in thepresence of a palladium catalyst, such as Xphos Pd G2, and a base, suchas potassium phosphate), Negishi and Stille (e.g., in the presence of apalladium(O) catalyst, such astetrakis(triphenylphosphine)palladium(0)), Cu-catalyzed amination (e.g.,in the presence of Cu catalyst and a ligand, such as CuI andphenanthroline, and a base, such as cesium carbonate or potassiumcarbonate), and others, to give the compounds of Formula 1-3.Deprotection of the protecting group (e.g., under acidic conditions,such as treatment with HCl or TFA) results in the formation of compoundsof Formula 1-4. These compounds can be further halogenated with one ofthe halogenation agents (e.g., NIS or iodine) to form compounds ofFormula 1-5. The NH group of the pyrazole ring of the compounds ofFormula 1-5 is protected with a suitable protecting group, such as Bocor SEM, to form compounds of Formula 1-6. The halogen substituent in thecompounds of Formula 1-6 can be converted into R¹ via a number ofdifferent cross-coupling reactions, including Stille (ACS Catalysis2015, 5, 3040-3053) Suzuki (Tetrahedron 2002, 58, 9633-9695),Sonogashira (Chem. Soc. Rev. 2011, 40, 5084-5121), Negishi (ACSCatalysis 2016, 6, 1540-1552), Buchwald-Hartwig amination (Chem. Sci.2011, 2, 27-50), Cu-catalyzed amination (Org. React. 2014, 85, 1-688)and others, to give the compounds of Formula 1-7. Finally, deprotectionof the protecting group under acidic conditions (e.g., treatment withHCl or TFA) results in the formation of the desired compounds of Formula(I).

Alternatively, to install various substitutions at position Cy^(A),compounds of Formula (I) can be prepared using a process as illustratedin Scheme 2. Iodination of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine 1-1with one of the iodination agents, such as iodine or NIS, formscompounds of Formula 2-2. The NH group of the pyrazole ring of thecompounds of Formula 2-2 is protected with a suitable protecting group(e.g., Boc or SEM) to form compounds of Formula 2-3. The iodosubstituent in the compounds of Formula 2-3 can be converted into R¹ viaa number of different cross-coupling reactions, including Suzuki,Sonogashira, Negishi, Buchwald-Hartwig amination, Cu-catalyzed aminationand others, to give the compounds of Formula 2-4. The chloro substituentin the compounds of Formula 2-4 can be further converted into Cy^(A) viaa number of different cross-coupling reactions, including Suzuki,Stille, Negishi, Cu-catalyzed amination and others, to give thecompounds of Formula 2-5. Finally, deprotection of the protecting group,e.g. under acidic conditions, such as treatment with HCl or TFA, resultsin the formation of the desired compounds of Formula (I).

Compounds of Formula (Ia) (compounds of Formula I wherein R¹ isNR^(c)C(O)R^(b)) can be prepared, using a process as illustrated inScheme 3. In the process depicted in Scheme 3, compounds of Formula 1-6reacts with an amine, e.g. (4-methoxyphenyl)methanamine, under standardBuchwald-Hartwig amination conditions (e.g. Pd-catalyst, such as RuphosPd G2, and a base, such as cesium carbonate) to form compounds ofFormula 3-2. Deprotection of the protecting groups (e.g., under acidicconditions, such as treatment with TFA) results in the formation ofcompounds of Formula 3-3. The NH group of the pyrazole ring of thecompounds of Formula 3-3 is protected with a suitable protecting group(e.g., Boc) to form compounds of Formula 3-4. Compounds of Formula 3-4react with different acid chlorides in a presence of base, such astriethylamine or DIPEA, to form compounds of Formula 3-5.

Finally, deprotection of the protecting group, e.g. under acidicconditions, such as treatment with HCl or TFA, results in the formationof the desired compounds of Formula (Ia). Alternatively compounds ofFormula 3-5 can be alkylated or arylated and then deprotected to prepareamides wherein R^(c) is other than hydrogen.

Compounds of Formula (Ib) (compounds of Formula I wherein R¹ isC(O)NR^(c)R^(d)) can be prepared, using a process as illustrated inScheme 4. In the process depicted in Scheme 4, compounds of Formula 1-6are converted into compounds of formula 4-2 under Pd-catalyzedcarbonylation conditions, such as in a presence of Pd catalyst (e.g.Pd(dppf)Cl₂*DCM) and base (e.g., triethylamine) under carbon monoxideatmosphere. Hydrolysis of the ester group under basic conditions, suchas LiOH or NaOH, forms the compounds of Formula 4-3. Compounds of theFormula 4-3 can be coupled to an amine, HNR^(c)R^(d), using standardamide coupling agents (e.g., HBTU, HATU or EDC) to give compounds ofFormula 4-4. Finally, deprotection of the protecting group, e.g. underacidic conditions, such as treatment with HCl or TFA, results in theformation of the desired compounds of Formula (Ib).

HPK1 Kinase

Extensive studies have established that HPK1 is a negative regulator ofT cell and B cell activation (Hu, M. C., et al., Genes Dev, 1996.10(18): p. 2251-64; Kiefer, F., et al., EMBO J, 1996. 15(24): p.7013-25). HPK1-deficient mouse T cells showed dramatically increasedactivation of TCR proximal signaling, enhanced IL-2 production, andhyper-proliferation in vitro upon anti-CD3 stimulation (Shui, J. W., etal., Nat Immunol, 2007. 8(1): p. 84-91). Similar to T cells, HPK1knockout B cells produced much higher levels of IgM and IgG isoformsafter KLH immunization and displayed hyper-proliferation potentially asa result of enhanced BCR signaling. Wang, X., et al., J Biol Chem, 2012.287(14): p. 11037-48. Mechanistically, during TCR or BCR signaling, HPK1is activated by LCK/ZAP70 (T cells) or SYK/LYN (B cells) mediated-Tyr379phosphorylation and its subsequent binding to adaptor protein SLP-76 (Tcells) or BLNK (B cells) (Wang, X., et al., J Biol Chem, 2012. 287(14):p. 11037-48). Activated HPK1 phosphorylates SLP-76 on Ser376 or BLNK onThr152, leading to the recruitment of signaling molecule 14-3-3 andultimate ubiquitination-mediated degradation of SLP-76 or BLNK (Liou,J., et al., Immunity, 2000. 12(4): p. 399-408; Di Bartolo, V., et al., JExp Med, 2007. 204(3): p. 681-91). As SLP-76 and BLNK are essential forTCR/BCR-mediated signaling activation (e.g. ERK, phospholipase Cγ1,calcium flux, and NFAT activation), HPK1-mediated downregulation ofthese adaptor proteins provide a negative feedback mechanism toattenuate signaling intensity during T cell or B cell activation (Wang,X., et al., J Biol Chem, 2012. 287(14): p. 11037-48).

The bone marrow-derived dendritic cells (BDMCs) from HPK1 knockout miceshowed higher expression of co-stimulatory molecules (e.g. CD80/CD86)and enhanced production of proinflammatory cytokines (IL-12, TNF-α etc),and demonstrated superior ability to stimulate T cell proliferation invitro and in vivo as compared to wild-type DCs (Alzabin, S., et al., JImmunol, 2009. 182(10): p. 6187-94). These data suggest that HPK1 isalso an important negative regulator of dendritic cell activation(Alzabin, S., et al., J Immunol, 2009. 182(10): p. 6187-94). However,the signaling mechanisms underlying HPK-1 mediated negative regulationof DC activation remains to be elucidated.

In contrast, HPK1 appears to be a positive regulator of suppressivefunctions of regulatory T cells (Treg) (Sawasdikosol, S. et al., Thejournal of immunology, 2012. 188 (supplement 1): p. 163). HPK1 deficientmouse Foxp3+ Tregs were defective in suppressing TCR-induced effector Tcell proliferation, and paradoxically gained the ability to produce IL-2following TCR engagement (Sawasdikosol, S. et al., The Journal ofImmunology, 2012. 188 (supplement 1): p. 163). These data suggest thatHPK1 is an important regulator of Treg functions and peripheralself-tolerance.

HPK1 was also involved in PGE2-mediated inhibition of CD4+ T cellactivation (Ikegami, R., et al., J Immunol, 2001. 166(7): p. 4689-96).Studies published in US 2007/0087988 indicated that HPK1 kinase activitywas increased by exposure to physiological concentrations of PGE2 inCD4+ T cells and this effect was mediated by PEG2-induced PKAactivation. The proliferation of HPK1 deficient T cells was resistant tothe suppressive effects of PGE2 (see US 2007/0087988). Therefore,PGE2-mediated activation of HPK1 may represent a novel regulatorypathway of modulating immune response.

The present disclosure provides methods of modulating (e.g., inhibiting)HPK1 activity, said method comprising administering to a patient acompound provided herein, or a pharmaceutically acceptable salt thereof.In certain embodiments, the compounds of the present disclosure, orpharmaceutically acceptable salts thereof, are useful for therapeuticadministration to enhance, stimulate and/or increase immunity in cancer.For example, a method of treating a disease or disorder associated withinhibition of HPK1 interaction can include administering to a patient inneed thereof a therapeutically effective amount of a compound providedherein, or a pharmaceutically acceptable salt thereof. The compounds ofthe present disclosure can be used alone, in combination with otheragents or therapies or as an adjuvant or neoadjuvant for the treatmentof diseases or disorders, including cancers. For the uses describedherein, any of the compounds of the disclosure, including any of theembodiments thereof, may be used.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, triple-negativebreast cancer, colon cancer and lung cancer (e.g. non-small cell lungcancer and small cell lung cancer). Additionally, the disclosureincludes refractory or recurrent malignancies whose growth may beinhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

In some embodiments, diseases and indications that are treatable usingthe compounds of the present disclosure include, but are not limited tohematological cancers, sarcomas, lung cancers, gastrointestinal cancers,genitourinary tract cancers, liver cancers, bone cancers, nervous systemcancers, gynecological cancers, and skin cancers.

Exemplary hematological cancers include lymphomas and leukemias such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL),chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma(DLBCL), mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsedor refractory NHL and recurrent follicular), Hodgkin lymphoma,myeloproliferative diseases (e.g., primary myelofibrosis (PMF),polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplasiasyndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiplemyeloma, cutaneous T-cell lymphoma, Waldenstrom's Macroglubulinemia,hairy cell lymphoma, chronic myelogenic lymphoma and Burkitt's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma,osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma,myxoma, rhabdomyoma, rhabdosarcoma, fibroma, lipoma, harmatoma, andteratoma.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), smallcell lung cancer, bronchogenic carcinoma (squamous cell,undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,chondromatous hamartoma, and mesothelioma.

Exemplary gastrointestinal cancers include cancers of the esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma), and colorectal cancer.

Exemplary genitourinary tract cancers include cancers of the kidney(adenocarcinoma, Wilm's tumor [nephroblastoma]), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), and testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma).

Exemplary liver cancers include hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, and hemangioma.

Exemplary bone cancers include, for example, osteogenic sarcoma(osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma,chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cellsarcoma), multiple myeloma, malignant giant cell tumor chordoma,osteochronfroma (osteocartilaginous exostoses), benign chondroma,chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant celltumors

Exemplary nervous system cancers include cancers of the skull (osteoma,hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,meduoblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma,glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,congenital tumors), and spinal cord (neurofibroma, meningioma, glioma,sarcoma), as well as neuroblastoma and Lhermitte-Duclos disease.

Exemplary gynecological cancers include cancers of the uterus(endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervicaldysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma,mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecalcell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignantteratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma),and fallopian tubes (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamouscell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, molesdysplastic nevi, lipoma, angioma, dermatofibroma, and keloids. In someembodiments, diseases and indications that are treatable using thecompounds of the present disclosure include, but are not limited to,sickle cell disease (e.g., sickle cell anemia), triple-negative breastcancer (TNBC), myelodysplastic syndromes, testicular cancer, bile ductcancer, esophageal cancer, and urothelial carcinoma.

Exemplary head and neck cancers include glioblastoma, melanoma,rhabdosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinomas,adenocarcinomas, oral cancer, laryngeal cancer, nasopharyngeal cancer,nasal and paranasal cancers, thyroid and parathyroid cancers.

In some embodiments, HPK1 inhibitors may be used to treat tumorsproducing PGE2 (e.g. Cox-2 overexpressing tumors) and/or adenosine (CD73and CD39 over-expressing tumors). Overexpression of Cox-2 has beendetected in a number of tumors, such as colorectal, breast, pancreaticand lung cancers, where it correlates with a poor prognosis.Overexpression of COX-2 has been reported in hematological cancer modelssuch as RAJI (Burkitt's lymphoma) and U937 (acute promonocytic leukemia)as well as in patient's blast cells. CD73 is up-regulated in varioushuman carcinomas including those of colon, lung, pancreas and ovary.Importantly, higher expression levels of CD73 are associated with tumorneovascularization, invasiveness, and metastasis and with shorterpatient survival time in breast cancer.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Examples of agents that may be combined with compounds ofthe present disclosure include inhibitors of the PI3K-AKT-mTOR pathway,inhibitors of the Raf-MAPK pathway, inhibitors of JAK-STAT pathway,inhibitors of beta catenin pathway, inhibitors of notch pathway,inhibitors of hedgehog pathway, inhibitors of Pim kinases, andinhibitors of protein chaperones and cell cycle progression. Targetingmore than one signaling pathway (or more than one biological moleculeinvolved in a given signaling pathway) may reduce the likelihood ofdrug-resistance arising in a cell population, and/or reduce the toxicityof treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors for the treatmentof diseases, such as cancer. Examples of cancers include solid tumorsand liquid tumors, such as blood cancers. For example, the compounds ofthe present disclosure can be combined with one or more inhibitors ofthe following kinases for the treatment of cancer: Akt1, Akt2, Akt3,TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK,MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR,CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4,c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2,EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK,ABL, ALK and B-Raf. In some embodiments, the compounds of the presentdisclosure can be combined with one or more of the following inhibitorsfor the treatment of cancer. Non-limiting examples of inhibitors thatcan be combined with the compounds of the present disclosure fortreatment of cancers include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 orFGFR4, e.g., AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258,lucitanib, dovitinib, TAS-120, JNJ-42756493, Debiol347, INCB54828,INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g.,ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g.,epacadostat and NLG919), an LSD 1 inhibitor (e.g., GSK2979552, INCB59872and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor (e.g., INCB50797and INCB50465), a PI3K-gamma inhibitor such as a PI3K-gamma selectiveinhibitor, a CSFIR inhibitor (e.g., PLX3397 and LY3022855), a TAMreceptor tyrosine kinases (Tyro-3, Axl, and Mer), an angiogenesisinhibitor, an interleukin receptor inhibitor, bromo and extra terminalfamily members inhibitors (for example, bromodomain inhibitors or BETinhibitors such as OTX015, CPI-0610, INCB54329 and INCB57643) and anadenosine receptor antagonist or combinations thereof. Inhibitors of HDAC such as panobinostat and vorinostat. Inhibitors of c-Met such asonartumzumab, tivantnib, and INC-280. Inhibitors of BTK such asibrutinib. Inhibitors of mTOR such as rapamycin, sirolimus,temsirolimus, and everolimus. Inhibitors of Raf, such as vemurafenib anddabrafenib. Inhibitors of MEK such as trametinib, selumetinib andGDC-0973. Inhibitors of Hsp90 (e.g., tanespimycin), cyclin dependentkinases (e.g., palbociclib), PARP (e.g., olaparib) and Pim kinases(LGH447, INCB053914 and SGI-1776) can also be combined with compounds ofthe present disclosure.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors. Exemplary immune checkpointinhibitors include inhibitors against immune checkpoint molecules suchas CD20, CD27, CD28, CD39, CD40, CD122, CD96, CD73, CD47, OX40, GITR,CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1,PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule isa stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR and CD137. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3,B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In someembodiments, the compounds provided herein can be used in combinationwith one or more agents selected from KIR inhibitors, TIGIT inhibitors,LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab. In some embodiments, the anti PD-1 antibody isSHR-1210.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CSF1R, e.g., an anti-CSF1R antibody. In someembodiments, the anti-CSF1R antibody is IMC-CS4 or RG7155.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016, LAG525, IMP321 or GSK2831781.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518, MK-4166, MK1248, BMS-986156, MEDI1873or GWN323.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562,MEDI6469, MOXR0916, PF-04518600 or GSK3174998. In some embodiments, theOX40L fusion protein is MEDI6383.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of TIM3, e.g., an anti-TIM3 antibody. In some embodiments,the anti-TIM3 antibody is MBG-453.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CD20, e.g., an anti-CD20 antibody. In some embodiments,the anti-CD20 antibody is obinutuzumab or rituximab.

In some embodiments, the compounds of the invention can be used incombination with one or more metabolic enzyme inhibitors. In someembodiments, the metabolic enzyme inhibitor is an inhibitor of IDO1,TDO, or arginase. Examples of IDO1 inhibitors include epacadostat andNGL919. An example of an arginase inhibitor is CB-1158.

The compounds of the present disclosure can be used in combination withbispecific antibodies. In some embodiments, one of the domains of thebispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3,CD137, ICOS, CD3 or TGFβ receptor.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include bendamustine, nitrogen mustards, ethylenimine derivatives,alkyl sulfonates, nitrosoureas and triazenes, uracil mustard,chlormethine, cyclophosphamide (Cytoxan™), ifosfamide, melphalan,chlorambucil, pipobroman, triethylene-melamine,triethylenethiophosphoramine, busulfan, carmustine, lomustine,streptozocin, dacarbazine, and temozolomide. In some embodiments, theproteasome inhibitor is carfdzomib. In some embodiments, thecorticosteroid is dexamethasone (DEX). In some embodiments, theimmunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, oncolytic virotherapy and immunomodulating small molecules,including thalidomide or JAK1/2 inhibitor and the like. The compoundscan be administered in combination with one or more anti-cancer drugs,such as a chemotherapeutics. Example chemotherapeutics include any of:abarelix, abiraterone, afatinib, aflibercept, aldesleukin, alemtuzumab,alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide,asparaginase, axitinib, azacitidine, bevacizumab, bexarotene,baricitinib, bicalutamide, bleomycin, bortezombi, bortezomib, brivanib,buparlisib, busulfan intravenous, busulfan oral, calusterone,capecitabine, carboplatin, carmustine, cediranib, cetuximab,chlorambucil, cisplatin, cladribine, clofarabine, crizotinib,cyclophosphamide, cytarabine, dacarbazine, dacomitinib, dactinomycin,dalteparin sodium, dasatinib, dactinomycin, daunorubicin, decitabine,degarelix, denileukin, denileukin diftitox, deoxycoformycin,dexrazoxane, docetaxel, doxorubicin, droloxafine, dromostanolonepropionate, eculizumab, enzalutamide, epidophyllotoxin, epirubicin,erlotinib, estramustine, etoposide phosphate, etoposide, exemestane,fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil,flutamide, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin,goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin,idelalisib, ifosfamide, imatinib mesylate, interferon alfa 2a,irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin,leuprolide acetate, levamisole, lomustine, meclorethamine, megestrolacetate, melphalan, mercaptopurine, methotrexate, methoxsalen,mithramycin, mitomycin C, mitotane, mitoxantrone, nandrolonephenpropionate, navelbene, necitumumab, nelarabine, neratinib,nilotinib, nilutamide, nofetumomab, oserelin, oxaliplatin, paclitaxel,pamidronate, panitumumab, pazopanib, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pilaralisib, pipobroman, plicamycin,ponatinib, prednisone, procarbazine, quinacrine, rasburicase,regorafenib, reloxafine, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, tegafur,temozolomide, teniposide, testolactone, thalidomide, thioguanine,thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin,triptorelin, uracil mustard, valrubicin, vandetanib, vinblastine,vincristine, vinorelbine, vorinostat and zoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab or tremelimumab), 4-1BB, antibodies to PD-1 andPD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Examples ofantibodies to PD-1 and/or PD-L1 that can be combined with compounds ofthe present disclosure for the treatment of cancer or infections such asviral, bacteria, fungus and parasite infections include, but are notlimited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

Other anti-cancer agents include inhibitors of kinases associated cellproliferative disorder. These kinases include but not limited toAurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptorkinases, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3,JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk and SGK.

Other anti-cancer agents also include those that block immune cellmigration such as antagonists to chemokine receptors, including CCR2 andCCR4.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present disclosure can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddl);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′, 3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione);and (+)-calanolide A (NSC-675451) and B. Typical suitable proteaseinhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538);indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94); lasinavir(BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Otherantiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside and Yissum Project No. 11607.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus the present disclosure provides a compositioncomprising a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or a pharmaceutically acceptable salt thereof, or any of the embodimentsthereof, and at least one pharmaceutically acceptable carrier orexcipient. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the micro crystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methyl cellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/or hydroxypropylmethylcellulose 2208 K100LV (e.g., Methocel K00LV™). In someembodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydro phobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

Labeled Compounds and Assay Methods

The compounds of the present disclosure can further be useful ininvestigations of biological processes in normal and abnormal tissues.Thus, another aspect of the present invention relates to fluorescentdye, spin label, heavy metal or radio-labeled compounds provided hereinthat would be useful not only in imaging techniques but also in assays,both in vitro and in vivo, for localizing and quantitating HPK1 proteinin tissue samples, including human, and for identifying HPK1 ligands byinhibition binding of a labeled compound. Accordingly, the presentinvention includes HPK1 binding assays that contain such labeledcompounds.

The present invention further includes isotopically-substitutedcompounds of the disclosure. An “isotopically-substituted” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having the same atomic number but a differentatomic mass or mass number. Compounds of the invention may containisotopes in a natural abundance as found in nature. Compounds of theinvention may also have isotopes in amounts greater to that found innature, e.g., synthetically incorporating low natural abundance isotopesinto the compounds of the invention so they are enriched in aparticularly useful isotope (e.g., ²H and ¹³C). It is to be understoodthat a “radio-labeled” compound is a compound that has incorporated atleast one isotope that is radioactive (e.g., radionuclide), e.g., ³H and¹⁴C. Suitable radionuclides that may be incorporated in compounds of thepresent invention include but are not limited to ³H (also written as Tfor tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl,⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵I and ¹³¹I. The radionuclide thatis incorporated in the instant radio-labeled compounds will depend onthe specific application of that radio-labeled compound. In someembodiments, the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. For in vitro HPK1 labeling and competitionassays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, or ³⁵Swill generally be most useful. For radio-imaging applications ¹¹C, ¹⁸F,¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br will generally be mostuseful. Synthetic methods for incorporating radio-isotopes into organiccompounds are known in the art.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a HPK1 protein bymonitoring its concentration variation when contacting with the HPK1,through tracking of the labeling. For example, a test compound (labeled)can be evaluated for its ability to reduce binding of another compoundwhich is known to bind to a HPK1 protein (i.e., standard compound).Accordingly, the ability of a test compound to compete with the standardcompound for binding to the HPK1 protein directly correlates to itsbinding affinity. Conversely, in some other screening assays, thestandard compound is labeled and test compounds are unlabeled.Accordingly, the concentration of the labeled standard compound ismonitored in order to evaluate the competition between the standardcompound and the test compound, and the relative binding affinity of thetest compound is thus ascertained.

Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of HPK1, such as cancer or infections, which include one ormore containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or any ofthe embodiments thereof. Such kits can further include one or more ofvarious conventional pharmaceutical kit components, such as, e.g.,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of HPK1 according to at least one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Preparatory LC-MS purifications of some of the compounds preparedwere performed on Waters mass directed fractionation systems. The basicequipment setup, protocols, and control software for the operation ofthese systems have been described in detail in the literature. See e.g.“Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K.Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MSConfigurations and Methods for Parallel Synthesis Purification”, K.Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi.Chem., 5, 670 (2003); and “Preparative LC-MS Purification: ImprovedCompound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A.Combs, J. Combi. Chem., 6, 874-883 (2004). The compounds separated weretypically subjected to analytical liquid chromatography massspectrometry (LCMS) for purity check under the following conditions:Instrument; Agilent 1100 series, LC/MSD, Column: Waters Sunfire™ C₁₈ 5μm particle size, 2.1×5.0 mm, Buffers: mobile phase A: 0.025% TFA inwater and mobile phase B: acetonitrile; gradient 2% to 80% of B in 3minutes with flow rate 2.0 mL/minute.

Some of the compounds prepared were also separated on a preparativescale by reverse-phase high performance liquid chromatography (RP-HPLC)with MS detector or flash chromatography (silica gel) as indicated inthe Examples. Typical preparative reverse-phase high performance liquidchromatography (RP-HPLC) column conditions are as follows:

pH=2 purifications: Waters Sunfire™ C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.1% TFA (trifluoroacetic acid) inwater and mobile phase B: acetonitrile; the flow rate was 30 mL/minute,the separating gradient was optimized for each compound using theCompound Specific Method Optimization protocol as described in theliterature [see “Preparative LCMS Purification: Improved CompoundSpecific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs,J. Comb. Chem., 6, 874-883 (2004)]. Typically, the flow rate used withthe 30×100 mm column was 60 mL/minute.

pH=10 purifications: Waters XBridge C₁₈ 5 μm particle size, 19×100 mmcolumn, eluting with mobile phase A: 0.15% NH₄OH in water and mobilephase B: acetonitrile; the flow rate was 30 mL/minute, the separatinggradient was optimized for each compound using the Compound SpecificMethod Optimization protocol as described in the literature [See“Preparative LCMS Purification: Improved Compound Specific MethodOptimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem.,6, 874-883 (2004)]. Typically, the flow rate used with 30×100 mm columnwas 60 mL/minute.

Example 1.5-(2-Fluorophenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-d]pyrimidine

Step 1. 5-Chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine

Potassium hydroxide (2.2 g, 39 mmol) and iodine (4.9 g, 19 mmol) wereadded to a solution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (Astatech,1.5 g, 9.7 mmol) in 1,4-dioxane (20 mL). The reaction mixture wasstirred at 50° C. for 2 hours. After cooling to r.t., water was addedand the reaction was neutralized to pH 7. The mixture was then extractedwith ethyl acetate and the organic phase was washed with brine. Theorganic phase was dried over sodium sulfate and the solvents wereevaporated under reduced pressure. The crude product was purified byBiotage Isolera™ (1 g, 37%). LCMS calculated for C₅H₃ClIN₄ (M+H)⁺m/z=280.9; found 281.0.

Step 2.5-Chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine

NaH in mineral oil (150 mg, 3.8 mmol) was slowly added at 0° C. to asolution of 5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine (964 mg, 3.44mmol) and [(3-(trimethylsilyl)ethoxy]methyl chloride (639 μL, 3.61 mmol)in tetrahydrofuran (10 mL). After stirring at r.t. for 1 h, the reactionmixture was quenched by the addition of water and the resulting mixturewas extracted with ethyl acetate. The organic phase was washed withbrine and dried over sodium sulfate. The solvents were evaporated underreduced pressure and the crude product was purified by Biotage Isolera™(1.2 g, 88%). LCMS calculated for C₁₁H₁₇ClIN₄OSi (M+H)⁺ m/z=411.0; found411.0.

Step 3.5-Chloro-3-[4-(4-methylpiperazin-1-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine

5-Chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine(636 mg, 1.55 mmol), [4-(4-methylpiperazin-1-yl)phenyl]boronic acid (340mg, 1.5 mmol),[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) complexedwith dichloromethane (1:1) (100 mg, 0.2 mmol), potassium phosphate (430mg, 2.0 mmol) and a magnet bar were placed in a vial. The vial wassealed with a Teflon screw-cap, evacuated and backfilled with nitrogen(this process was repeated a total of three times). After dioxane (12mL) and degassed water (2 mL) were added, the mixture was heated at 100°C. for 16 h. The reaction mixture was then diluted with ethyl acetate,washed with brine and dried over sodium sulfate. The solvents wereevaporated under reduced pressure and the crude product was purified byBiotage Isolera™ (520 mg, 74%). LCMS calculated for C₂₂H₃₂ClN₆OSi (M+H)⁺m/z=459.2; found 459.3.

Step 4.5-(2-Fluorophenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-d]pyrimidine

5-Chloro-3-[4-(4-methylpiperazin-1-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine(15 mg, 0.033 mmol), (2-fluorophenyl)boronic acid (6.8 mg, 0.049 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.6 mg, 0.0033 mmol), potassium phosphate (21 mg, 0.098mmol) and a magnet bar were placed in a vial with septum which was thenevacuated and backfilled with nitrogen three times. 1,4-Dioxane (2.5 mL)and degassed water (0.3 mL) were added and the reaction mixture wasstirred at 80° C. for 1 h. Then 1M solution of HCl in water (1 mL) and4M solution of HCl in dioxane (1 mL) were added and reaction was stirredat 80° C. for 1 h. Methanol (1 mL) was added and reaction was furtherstirred at 80° C. for 30 min. The reaction mixture was then diluted withacetonitrile and was purified with prep-LCMS (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LCMS calculated for C₂₂H₂₂FN₆ (M+H)⁺:m/z=389.2; Found: 389.3.

Example 2.3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-o-tolyl-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 1, using o-tolylboronic acid, instead of (2-fluorophenyl)boronicacid as starting material. LCMS calculated for C₂₃H₂₅N₆ (M+H)⁺:m/z=385.2; Found: 385.3.

Example 3.5-(2-Methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 1, using 2-methoxyphenylboronic acid, instead of(2-fluorophenyl)boronic acid as starting material. LCMS calculated forC₂₃H₂₅N₆O (M+H)⁺: m/z=401.2; Found: 401.3.

Example 4.5-(2-Chloro-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 1, using 2-chloro-6-fluorophenylboronic acid, instead of(2-fluorophenyl)boronic acid as starting material. LCMS calculated forC₂₂H₂₁ClFN₆ (M+H)⁺: m/z=423.2; Found: 423.2.

Example 5.3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 1, using pyridin-3-ylboronic acid, instead of(2-fluorophenyl)boronic acid as starting material. LCMS calculated forC₂₁H₂₂N₇ (M+H)⁺: m/z=372.2; Found: 372.3.

Example 6.3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(5-methylpyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 1, using 5-methylpyridin-3-ylboronic acid, instead of(2-fluorophenyl)boronic acid as starting material. LCMS calculated forC₂₂H₂₄N₇ (M+H)⁺: m/z=386.2; Found: 386.2.

Example 7.6-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)isoindolin-1-one

This compound was prepared according to the procedures described inExample 1, using6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one, insteadof (2-fluorophenyl)boronic acid as starting material. LCMS calculatedfor C₂₄H24N₇O (M+H)⁺: m/z=426.2; Found: 426.2.

Example 8.(5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)pyridin-3-yl)(morpholino)methanone

This compound was prepared according to the procedures described inExample 1, usingmorpholino(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanone,instead of (2-fluorophenyl)boronic acid as starting material. LCMScalculated for C₂₆H₂₉N₈O₂ (M+H)⁺: m/z=485.2; Found: 485.2.

Example 9.N-Methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)nicotinamide

This compound was prepared according to the procedures described inExample 1, usingN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide,instead of (2-fluorophenyl)boronic acid as starting material. LCMScalculated for C₂₃H₂₅N₈O (M+H)⁺: m/z=429.2; Found: 429.3.

Example 10.5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

This compound was prepared according to the procedures described inExample 1, using tert-butyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate,instead of (2-fluorophenyl)boronic acid as starting material. LCMScalculated for C₂₅H₂₈N₇ (M+H)⁺: m/z=426.2; Found: 426.2.

Example 11.5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 1, using 2-fluoro-6-methoxyphenylboronic acid, instead of(2-fluorophenyl)boronic acid as starting material. LCMS calculated forC₂₃H₂₄FN₆O (M+H)⁺: m/z=419.2; Found: 419.3.

Example 12.5-(2-Fluoro-6-methoxyphenyl)-3-phenyl-1H-pyrazolo[4,3d]pyrimidine

Step 1.5-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine

NaH in mineral oil (570 mg, 14 mmol) was slowly added at 0° C. to asolution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (2.0 g, 13 mmol) and[β-(trimethylsilyl)ethoxy]methyl chloride (2.40 mL, 13.6 mmol) intetrahydrofuran (25 mL). After stirring at r.t. for 1 h, the reactionmixture was quenched by the addition of water and the resulting mixturewas extracted with ethyl acetate. The organic phase was washed withbrine and dried over sodium sulfate. The solvents were evaporated underreduced pressure and the crude product was purified by Biotage Isolera™(2.36 g, 64%). LCMS calculated for C₁₁H₁₈ClN₄OSi (M+H)⁺ m/z=285.1; found285.2.

Step 2.5-(2-Fluoro-6-methoxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine

5-Chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine(2.36 g, 8.29 mmol), (2-fluoro-6-methoxyphenyl)boronic acid (2.1 g, 12mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (400 mg, 0.5 mmol), potassium phosphate (3.6 g, 17 mmol)and a magnet bar were placed in a flask. The flask was sealed with arubber cap, evacuated and backfilled with nitrogen (this process wasrepeated a total of three times). After dioxane (20 mL) and degassedwater (2 mL) were added, the mixture was heated at 90° C. for 1 h. Thereaction mixture was then diluted with ethyl acetate, washed with brineand dried over sodium sulfate. The solvents were evaporated underreduced pressure and the crude product was purified by Biotage Isolera™(3.27 g, 99%). LCMS calculated for C₁₈H₂₄FN₄O₂Si (M+H)⁺ m/z=375.2; found375.2.

Step 3. 5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine

A solution of5-(2-fluoro-6-methoxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine(3.27 g, 8.73 mmol) in a mixture of 1.0 M solution of hydrogen chloridein water (10 mL, 10 mmol) and 4.0 M solution of hydrogen chloride indioxane (10 mL, 42 mmol) was stirred at 80° C. for 1 h. Then methanol(10 mL) was added and the reaction mixture was further stirred at 80° C.for 30 min. After cooling to r.t., the reaction was neutralized to pH 7.The product was then extracted with ethyl acetate and the organic phasewas washed with brine. The organic phase was dried over sodium sulfateand the solvents were evaporated under reduced pressure. The crudeproduct was used in the next step without further purification. LCMScalculated for C₁₂H₁₀FN₄O (M+H)⁺ m/z=245.1; found 245.2.

Step 4. 5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidine

Potassium hydroxide (2.2 g, 39 mmol) and iodine (4.9 g, 19 mmol) wereadded to a solution of5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine (from previousstep) in 1,4-dioxane (20 mL). The reaction mixture was stirred at 50° C.for 2 hours. After cooling to r.t., water was added and reaction wasneutralized to pH 7. The product was then extracted with ethyl acetateand the organic phase was washed with a saturated solution of sodiumthiosulfate and brine. The organic phase was dried over sodium sulfateand the solvents were evaporated under reduced pressure. The crudeproduct was used in the next step without further purification. LCMScalculated for C₁₂H9FIN₄O (M+H)⁺ m/z=371.0; found 371.1.

Step 5.5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine

NaH in mineral oil (470 mg, 12 mmol) was slowly added at 0° C. to asolution of5-(2-fluoro-6-methoxyphenyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidine (fromprevious step) and [(3-(trimethylsilyl)ethoxy]methyl chloride (2.00 mL,11.3 mmol) in tetrahydrofuran (25 mL). After stirring at r.t. for 1 h,the reaction mixture was quenched by the addition of water and theproduct was extracted with ethyl acetate. The organic phase was washedwith brine and dried over sodium sulfate. The solvents were evaporatedunder reduced pressure and the crude product was purified by BiotageIsolera™ (900 mg, 20% over 3 steps). LCMS calculated for C₁₈H₂₃FIN₄O₂Si(M+H)⁺ m/z=501.1; found 501.0.

Step 6.5-(2-Fluoro-6-methoxyphenyl)-3-phenyl-1H-pyrazolo[4,3-d]pyrimidine

5-(2-Fluoro-6-methoxyphenyl)-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine(15 mg, 0.030 mmol), phenylboronic acid (5.5 mg, 0.045 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.4 mg, 0.0030 mmol), potassium phosphate (13 mg, 0.062mmol) and a magnet bar were placed in a vial with septum which was thenevacuated and backfilled with nitrogen three times. 1,4-Dioxane (1.5 mL)and degassed water (0.2 mL) were added and the reaction mixture wasstirred at 80° C. for 1 h. Then 1M solution of HCl in water (1 mL) and4M solution of HCl in dioxane (1 mL) were added, and reaction wasstirred at 80° C. for 1 h. Methanol (1 mL) was added and reaction wasfurther stirred at 80° C. for 30 min. The reaction mixture was thendiluted with acetonitrile and was purified with prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LCMS calculated for C₁₈H₁₄FN₄O (M+H)⁺:m/z=321.1; Found: 321.2.

Example 13.5-(2-Fluoro-6-methoxyphenyl)-3-(2-fluorophenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using 2-fluorophenylboronic acid, instead of phenylboronicacid as starting material. LCMS calculated for C₁₈H₁₃F₂N₄O (M+H)⁺:m/z=339.1; Found: 339.1.

Example 14.5-(2-Fluoro-6-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole,instead of phenylboronic acid as starting material. LCMS calculated forC₁₆H₁₄FN₆O (M+H)⁺: m/z=325.1; Found: 325.2.

Example 15.5-(2-Fluoro-6-methoxyphenyl)-3-(pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using pyridin-4-ylboronic acid, instead of phenylboronicacid as starting material. LCMS calculated for C₁₇H₁₃FN₅O (M+H)⁺:m/z=322.1; Found: 322.2.

Example 16.5-(2-Fluoro-6-methoxyphenyl)-3-(pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using pyrimidin-5-ylboronic acid, instead of phenylboronicacid as starting material. LCMS calculated for C₁₆H₁₂FN₆O (M+H)⁺:m/z=323.1; Found: 323.2.

Example 17.4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)benzonitrile

This compound was prepared according to the procedures described inExample 12, using 4-cyanophenylboronic acid, instead of phenylboronicacid as starting material. LCMS calculated for C₁₆H₁₂FN₆O (M+H)⁺:m/z=346.1; Found: 346.2.

Example 18.5-(2-Fluoro-6-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using 4-(trifluoromethyl)phenylboronic acid, instead ofphenylboronic acid as starting material. LCMS calculated for C₁₉H₁₃F₄N₄O(M+H)⁺: m/z=389.1; Found: 389.2.

Example 19.5-(2-Fluoro-6-methoxyphenyl)-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using 3-methoxyphenylboronic acid, instead of phenylboronicacid as starting material. LCMS calculated for C₁₉H₁₆FN₄O₂ (M+H)⁺:m/z=351.1; Found: 351.1.

Example 20.5-(2-Fluoro-6-methoxyphenyl)-3-O-tolyl-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using o-tolylboronic acid, instead of phenylboronic acid asstarting material. LCMS calculated for C₁₉H₁₆FN₄O (M+H)⁺: m/z=335.1;Found: 335.1.

Example 21.5-(2-Fluoro-6-methoxyphenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using thiophen-3-ylboronic acid, instead of phenylboronicacid as starting material. LCMS calculated for C₁₆H₁₂FN₄OS (M+H)⁺:m/z=327.1; Found: 327.1.

Example 22.4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)-N,N-dimethylbenzamide

This compound was prepared according to the procedures described inExample 12, usingN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide,instead of phenylboronic acid as starting material. LCMS calculated forC₂₁H₁₉FN₅O₂ (M+H)⁺: m/z=392.2; Found: 392.3.

Example 23.5-(2-Fluoro-6-methoxyphenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine,instead of phenylboronic acid as starting material. LCMS calculated forC₂₄H₂₆FN₆O (M+H)⁺: m/z=433.2; Found: 433.3.

Example 24.4-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)benzyl)morpholine

This compound was prepared according to the procedures described inExample 12, using4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine,instead of phenylboronic acid as starting material. LCMS calculated forC₂₃H₂₃FN₅O₂ (M+H)⁺: m/z=420.2; Found: 420.3.

Example 25.5-(2-Fluoro-6-methoxyphenyl)-3-(3-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using1-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine,instead of phenylboronic acid as starting material. LCMS calculated forC₂₄H₂₆FN₆O (M+H)⁺: m/z=433.2; Found: 433.3.

Example 26.4-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)phenyl)morpholine

This compound was prepared according to the procedures described inExample 12, using4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine,instead of phenylboronic acid as starting material. LCMS calculated forC₂₂H₂₁FN₅O₂ (M+H)⁺: m/z=406.2; Found: 406.3.

Example 27.5-(2-Fluoro-6-methoxyphenyl)-3-(3-(piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using tert-butyl4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate,instead of phenylboronic acid as starting material. LCMS calculated forC₂₂H₂₂FN₆O (M+H)⁺: m/z=405.2; Found: 405.2.

Example 28.5-(2-fluoro-6-methoxyphenyl)-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using 3-(pyrrolidin-1-yl)phenylboronic acid, instead ofphenylboronic acid as starting material. LCMS calculated for C₂₂H₂₁FN₅O(M+H)⁺: m/z=390.2; Found: 390.2.

Example 29.4-(3-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)phenyl)morpholine

This compound was prepared according to the procedures described inExample 12, using4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine,instead of phenylboronic acid as starting material. LCMS calculated forC₂₂H₂₁FN₅O₂ (M+H)⁺: m/z=406.2; Found: 406.2.

Example 30.3-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)-N,N-dimethylaniline

This compound was prepared according to the procedures described inExample 12, using 3-(dimethylamino)phenylboronic acid, instead ofphenylboronic acid as starting material. LCMS calculated for C₂₀H₁₉FN₅O(M+H)⁺: m/z=364.2; Found: 364.2.

Example 31.(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)(morpholino)methanone

This compound was prepared according to the procedures described inExample 12, using 4-(morpholine-4-carbonyl)phenylboronic acid, insteadof phenylboronic acid as starting material. LCMS calculated forC₂₃H₂₁FN₅O₃ (M+H)⁺: m/z=434.2; Found: 434.2.

Example 32.N-Cyclopentyl-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)benzamide

This compound was prepared according to the procedures described inExample 12, using 4-(cyclopentylcarbamoyl)phenylboronic acid, instead ofphenylboronic acid as starting material. LCMS calculated for C₂₄H₂₃FN₅O₂(M+H)⁺: m/z=432.2; Found: 432.3.

Example 33.4-(1-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)phenyl)cyclopropyl)morpholine

This compound was prepared according to the procedures described inExample 12, using4-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropyl)morpholine,instead of phenylboronic acid as starting material. LCMS calculated forC₂₅H₂₅FN₅O₂ (M+H)⁺: m/z=446.2; Found: 446.3.

Example 34.2-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)phenyl)acetonitrile

This compound was prepared according to the procedures described inExample 12, using 4-(cyanomethyl)phenylboronic acid, instead ofphenylboronic acid as starting material. LCMS calculated for C₂₀H₁₅FN₅O(M+H)⁺: m/z=360.1; Found: 360.1.

Example 35.5-(2-Fluoro-6-methoxyphenyl)-3-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using 4-methoxyphenylboronic acid, instead of phenylboronicacid as starting material. LCMS calculated for C₁₉H₁₆FN₄O₂ (M+H)⁺:m/z=351.1; Found: 351.1.

Example 36.5-(2-Fluoro-6-methoxyphenyl)-3-(4-fluorophenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using 4-fluorophenylboronic acid, instead of phenylboronicacid as starting material. LCMS calculated for C₁₈H₁₃F₂N₄O (M+H)⁺:m/z=339.1; Found: 339.2.

Example 37.3-(4-(4-Ethylpiperazin-1-yl)phenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine,instead of phenylboronic acid as starting material. LCMS calculated forC₂₄H₂₆FN₆O (M+H)⁺: m/z=433.2; Found: 433.3.

Example 38.4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)-N-methylbenzamide

This compound was prepared according to the procedures described inExample 12, using 4-(methylcarbamoyl)phenylboronic acid, instead ofphenylboronic acid as starting material. LCMS calculated for C₂₀H₁₇FN₅O₂(M+H)⁺: m/z=378.1; Found: 378.2.

Example 39.3-(4-Cyclopropylphenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using 4-cyclopropylphenylboronic acid, instead ofphenylboronic acid as starting material. LCMS calculated for C₂₁H₁₈FN₄O(M+H)⁺: m/z=361.2; Found: 361.2.

Example 40.5-(2-Fluoro-6-methoxyphenyl)-3-(4-(piperidin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine,instead of phenylboronic acid as starting material. LCMS calculated forC₂₃H₂₃FN₅O (M+H)⁺: m/z=404.2; Found: 404.2.

Example 41.(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)methanamine

This compound was prepared according to the procedures described inExample 12, using 4-(tert-butoxycarbonylamino)methyl)phenylboronic acid,instead of phenylboronic acid as starting material. LCMS calculated forC₁₉H₁₇FN₅O (M+H)⁺: m/z=350.1; Found: 350.0.

Example 42.2-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)phenyl)-2-methylpropanenitrile

This compound was prepared according to the procedures described inExample 12, using 4-(2-cyanopropan-2-yl)phenylboronic acid, instead ofphenylboronic acid as starting material. LCMS calculated for C₂₂H₁₉FN₅O(M+H)⁺: m/z=388.2; Found: 388.2.

Example 43.5-(2-Fluoro-6-methoxyphenyl)-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using4,4,5,5-tetramethyl-2-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1,3,2-dioxaborolane,instead of phenylboronic acid as starting material. LCMS calculated forC₂₃H22FN₄O₂ (M+H)⁺: m/z=405.2; Found: 405.2.

Example 44.5-(2,3-Difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 1, using (2,3-difluorophenyl)boronic acid, instead of(2-fluorophenyl)boronic acid as starting material. LC-MS calculated forC₂₂H₂₁F₂N₆ (M+H)⁺: m/z=407.2; Found 407.2.

Example 45.5-(2,3-Difluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 1, using (2,3-difluoro-6-methoxyphenyl)boronic, instead of(2-fluorophenyl)boronic acid as starting material. LC-MS calculated forC₂₃H₂₃F₂N₆O (M+H)⁺: m/z=437.2; Found 437.2.

Example 46.2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzamide

Step 1. Ethyl2-fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzoate

To a solution of5-chloro-3-[4-(4-methylpiperazin-1-yl)phenyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[4,3-d]pyrimidine(Example 1 Step 3, 0.100 g, 0.218 mmol) and(3-(ethoxycarbonyl)-2-fluorophenyl)boronic acid (0.092 g, 0.436 mmol) in1,4-dioxane (2.90 ml) and water (0.726 ml) was addedchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(0.017 g, 0.022 mmol) and potassium phosphate tribasic (0.092 g, 0.436mmol). The reaction mixture was degassed and stirred at 90° C. for 2hours. After cooling to r.t., the reaction was filtered and concentratedto dryness under reduced pressure. The residue was purified by BiotageIsolera™ using 0-10% DCM in methanol to afford the desired product asyellowish oil. LC-MS calculated for C₃₁H₄₀FN₆O₃Si (M+H)⁺: m/z=591.2;Found 591.2.

Step 2.2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzoicacid

To a solution of the above intermediate in methanol (0.726 ml) was addedpotassium hydroxide (0.122 g, 2.178 mmol), and the reaction mixture wasstirred at r.t. for 1 hour. After this time the reaction mixture wasconcentrated to dryness, diluted with ethyl acetate and washed with of1N water solution of HCl (10 mL) and brine. The organic layer was driedover MgSO₄, filtered and concentrated to dryness to afford a crudedesired product which was used in the next step without furtherpurification. LC-MS calculated for C₂₉H₃₆FN₆O₃Si (M+H)⁺: m/z=563.2;Found 563.2.

Step 3.2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzamide

To a solution of2-fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzoicacid (30 mg, 0.053 mmol) in DMF (1 mL) were added 2.0M solution ofammonia in ethanol (267 μl, 0.533 mmol) and MX-diisopropylethylamine(37.2 μL, 0.213 mmol), followed by the addition of HATU (81 mg, 0.213mmol). The reaction mixture was then stirred at. r.t. for 2 hours. Afterthis time 4M HCl solution in dioxane (1.3 mL, 5.33 mmol) and 1N HClsolution in water (1.1 mL, 1.066 mmol) were added and the mixture wasstirred for another 1 hour at 80° C. It was then cooled to r.t., dilutedwith methanol, filtered and purified by prep-HPLC. (XBridge C18 column,eluting with a gradient of acetonitrile/water containing 0.1% TFA, atflow rate of 60 mL/min). LC-MS calculated for C₂₃H₂₃FN₇O (M+H)⁺:m/z=432.2; Found 432.2.

Example 47.2-Fluoro-N-methyl-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzamide

This compound was prepared according to the procedures described inExample 46, using 2.0M solution of methylamine in THF instead of 2.0Msolution of ammonia in ethanol as starting material. LC-MS calculatedfor C₂₄H₂₅FN₇O (M+H)⁺: m/z=446.2; Found 446.2.

Example 48.5-(2-Fluoro-6-methoxyphenyl)-3-(1-phenyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using 1-phenyl-1H-pyrazol-4-ylboronic acid, instead ofphenylboronic acid as starting material. LCMS calculated for C₂₁H₁₆FN₆O(M+H)⁺: m/z=387.1; Found: 387.2.

Example 49.4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)-1-methylpyridin-2(1H)-one

This compound was prepared according to the procedures described inExample 12, using1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one,instead of phenylboronic acid as starting material. LCMS calculated forC₁₈H₁₅FN₅O₂ (M+H)⁺: m/z=352.1; Found: 352.2.

Example 50.5-(2-Fluoro-6-methoxyphenyl)-3-(2-(piperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine,instead of phenylboronic acid as starting material. LCMS calculated forC₂₁H₂₁FN₇O (M+H)⁺: m/z=406.2; Found: 406.2.

Example 51.5-(2-Fluoro-6-methoxyphenyl)-3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine,instead of phenylboronic acid as starting material. LCMS calculated forC₂₂H₂₃FN₇O (M+H)⁺: m/z=420.2; Found: 420.2.

Example 52.5-(2-Fluoro-6-methoxyphenyl)-3-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedures described inExample 12, using tert-butyl4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate,instead of phenylboronic acid as starting material. LCMS calculated forC₂₁H₂₁FN₇O (M+H)⁺: m/z=406.2; Found: 406.2.

Example 53.4-(5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)pyridin-2-yl)morpholine

This compound was prepared according to the procedures described inExample 12, using4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine,instead of phenylboronic acid as starting material. LCMS calculated forC₂₁H₂₀FN₆O₂ (M+H)⁺: m/z=407.2; Found: 407.2.

Example 54.1-(4-(5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one

This compound was prepared according to the procedures described inExample 12, using1-(4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one,instead of phenylboronic acid as starting material. LCMS calculated forC₂₃H₂₃FN₇O₂ (M+H)⁺: m/z=448.2; Found: 448.2.

Example 55.(E)-5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)styryl)-1H-pyrazolo[4,3-d]pyrimidine

Step 1.(E)-1-Methyl-4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenyl)piperazine

A mixture of 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (135 mg,0.875 mmol), 1-(4-bromophenyl)-4-methylpiperazine (186 mg, 0.729 mmol),bis(tri-t-butylphosphine)palladium (0) (18.6 mg, 0.036 mmol) andtriethylamine (0.203 mL, 1.46 mmol) in toluene (3.0 mL) was stirred at80° C. under nitrogen atmosphere for 4 h. After cooling to roomtemperature, the mixture was concentrated in vacuo. The crude waspurified by Biotage Isolera™ (eluting with a gradient 0-50% methanol inDCM) to give the desired product as yellow solid (109 mg, 46%). LCMScalculated for C₁₉H₃₀BN₂O₂ (M+H)⁺: m/z=329.2; Found: 329.2.

Step 2.(E)-5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)styryl)-1H-pyrazolo[4,3-d]pyrimidine

A mixture of5-(2-fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine(Example 12, Step 5, 56.0 mg, 0.112 mmol),(E)-1-methyl-4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)phenyl)piperazine(55.1 mg, 0.168 mmol),(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complexwith dichloromethane (1:1) (4.09 mg, 0.0056 mmol) and potassiumphosphate (47.5 mg, 0.224 mmol) in 1,4-dioxane (2.0 mL) and water (0.4mL) was stirred at 80° C. under nitrogen atmosphere for 18 h. Aftercooling to room temperature, the mixture was concentrated in vacuo. Thecrude mixture was then dissolved in DCM (2.0 mL) and TFA (2.0 mL) wasadded to the mixture at room temperature. After stirring for 2 h, themixture was concentrated in vacuo. Then, the crude mixture was dissolvedin MeOH (3.5 mL) and 10% aqueous NH₄OH solution (1.5 mL) was added.After stirring for 30 min, the reaction mixture was purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water (pH=2), at flow rate of 60 mL/min) to give thedesired product as yellow solid. LCMS calculated for C₂₅H₂₆FN₆O (M+H)⁺:m/z=445.2; Found: 445.3. ¹H NMR (600 MHz, DMSO-d₆) δ 9.89 (br, 1H), 9.40(s, 1H), 7.86 (d, J=16.5 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 7.50 (m, 1H),7.38 (d, J=16.5 Hz, 1H), 7.02 (m, 3H), 6.96 (t, J=8.6 Hz, 1H), 3.93 (m,2H), 3.73 (s, 3H), 3.45 (m, 2H), 3.14 (m, 2H), 3.02 (m, 2H), 2.86 (s,3H) ppm.

Example 56.6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

Step 1. 5-Bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline

To a solution of 5-bromo-6-fluoroisoquinoline (1.002 g, 4.433 mmol) inacetic acid (20.0 mL) at room temperature was added sodiumtetrahydroborate (592.0 mg, 15.65 mmol) portionwise. The mixture wasstirred at room temperature for 16 h, and then concentrated.

The residue was diluted with CH₂Cl₂ and washed with 2 M Na₂CO₃ (aq). Theseparated organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated to give a yellow oil, which was used directly in the nextstep without further purification. LCMS calculated for C₉H₁₀BrFN (M+H)⁺m/z=230.0; found 230.1.

Step 2. tert-Butyl5-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of 5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline (1.020g, 4.433 mmol) in CH₂Cl₂ (12.0 mL) was added di-tert-butyl dicarbonate(1.617 g, 7.409 mmol). The mixture was stirred at room temperature for 1h, and then concentrated. The residue was purified on silica gel (120 g,0-100% EtOAc in hexanes) to give the desired product as a white solid(1.119 g, 76% over two steps). LCMS calculated for C₁₄H₁₇BrFNNaO₂(M+Na)⁺ m/z=352.0; found 352.0.

Step 3. tert-Butyl6-fluoro-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl 5-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.119 g, 3.389 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (1.358 g,5.348 mmol), potassium acetate (1.101 g, 11.22 mmol), and[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (1:1) (298.6 mg, 0.366 mmol). The vial was sealed with aTeflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). 1,4-Dioxane (15.0 mL) wasadded via syringe. The mixture was heated at 100° C. for 16 h. Aftercooling to room temperature, the reaction mixture was diluted withCH₂Cl₂ and filtered. The filtrate was concentrated. The residue waspurified on silica gel (40 g, 0-100% EtOAc in hexanes) to give thedesired product as a pale yellow oil (1001 mg, 78%). LCMS calculated forC₂₀H₂₉BFNNaO₄ (M+Na)⁺ m/z=400.2; found 400.2.

Step 4.6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

To a screw-cap vial equipped with a magnetic stir bar was added5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine(Example 12, Step 5, 50.9 mg, 0.111 mmol), XPhos Pd G2 (9.5 mg, 0.012mmol) and K₃PO₄ (78.2 mg, 0.368 mmol). The vial was sealed with aTeflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of tert-butyl6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(44.9 mg, 0.119 mmol) in 1,4-dioxane (2.0 mL) was added via syringe,followed by degassed water (150.0 μL). The mixture was heated at 80° C.for 1 h. After cooling to room temperature, the reaction mixture wasdiluted with CH₂Cl₂ and filtered. The filtrate was concentrated. Theresidue was dissolved in methanol (3.00 mL) and treated with 4.0 M HClin dioxane (2.00 mL, 8.00 mmol). The mixture was stirred at 65° C. for 2h. After cooling to room temperature, the mixture was purified usingprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product as a yellow solid (22.4 mg). LCMS calculatedfor C₂₅H₂₇FN₇ (M+H)⁺: m/z=444.2; Found: 444.2.

Example 57.1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)phenyl)piperidin-3-ol

Step 1.4-(5-Chloro-1-(2-(trimethylsilyl)ethoxy)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenol

To a solution of5-chloro-3-iodo-1-((2-(trimethylsilyl)ethoy)methyl)-1H-pyrazolo[4,3-d]pyrimidine(4.0 g, 9.74 mmol, Example 1, Step 2) in dioxane (39.0 ml) and water(9.74 ml) was added potassium phosphate (4.13 g, 19.5 mmol) and(4-hydroxyphenyl)boronic acid (1.34 g, 9.74 mmol) followed by additionof PdCl₂(dppf) (0.795 g, 0.974 mmol). N₂ was bubbled through the mixturefor 5 mins, and then it was stirred at 90° C. for 2 hours. After thistime, the mixture was cooled to r.t. and then concentrated to dryness.The residue was purified by silica gel chromatography using 0-10%methanol in DCM to afford desired product as brownish oil (590 mg,16.1%). LC-MS calculated for C₁₇H₂₂ClN₄O₂Si (M+H)⁺: m/z=377.2; found377.1.

Step 2.4-(5-(2-Fluoro-6-methylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenol

To a solution of4-(5-chloro-1-((2-(trimethylsilyl)ethoy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenol(660 mg, 1.75 mmol) in dioxane (14 ml) and water (3.5 ml) was addedpotassium phosphate (742 mg, 3.50 mmol) and(2-fluoro-6-methylphenyl)boronic acid (404 mg, 2.63 mmol) followed bychloro(2-dicycloheylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (138 mg, 0.175 mmol). N₂ was bubbled through the mixturefor 5 mins and then it was stirred at 80° C. for 2 hours. After thistime the mixture was cooled to r.t. and then concentrated to dryness.The residue was purified by silica gel chromatography using 0-10%methanol in DCM to afford desired product as brownish oil (390 mg,49.4%). LC-MS calculated for C₂₄H₂₈FN₄O₂Si (M+H)⁺: m/z=451.2; found451.2.

Step 3.4-(5-(2-Fluoro-6-methylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyltrifluoromethanesulfonate

To a solution of4-(5-(2-fluoro-6-methylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenol(990 mg, 2.2 mmol) in DMF (22 ml) was added sodium hydride (132 mg, 3.30mmol, 60% in mineral oil). After stirring at r.t. for 10 min,N-phenyltrifluoromethanesulfonimide (942 mg, 2.64 mmol) was added. Theresulting solution was stirred at r.t. for 30 mins, and then quenched byNH₄Cl aq. solution. The product was then extracted with ethyl acetate.The organic layer was washed with water and brine, and then dried overMgSO₄, filtered and concentrated to dryness. The residue was purified bysilica gel chromatography using 0-100% ethyl acetate in hexanes toafford desired product as brownish oil (460 mg, 35.9%). LC-MS calculatedfor C₂₅H₂₇F4N₄O₄SSi (M+H)⁺: m/z=583.1; found 583.1.

Step 4.1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)piperidin-3-ol

To a solution of4-(5-(2-fluoro-6-methylphenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyltrifluoromethanesulfonate (30 mg, 0.051 mmol) in dioxane (8 mL) wasadded cesium carbonate (33.6 mg, 0.103 mmol) and piperidin-3-ol (26.0mg, 0.257 mmol). The mixture was degassed andchloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(4.00 mg, 5.15 μmol) was added. The resulting mixture was stirred at 90°C. for 2 hours. After this time, the mixture was filtered, and 4.0 M HClin dioxane (1 mL, 4 mmol) and 1 mL of water were added. The reactionmixture was stirred for another 1 hour at 80° C. After this time, 1 mLof methanol was added and the reaction mixture was stirred for another30 min at 80° C. The mixture was then diluted with acetonitrile,filtered and purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LC-MS calculated for C₂₃H₂₃FN₅O (M+H)⁺: m/z=404.2; found 404.2.

Example 58.1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)phenyl)piperidine-4-carbonitrile

This compound was prepared according to the procedure described inExample 57, using piperidine-4-carbonitrile instead of piperidin-3-ol asstarting material. LC-MS calculated for C₂₄H₂₂FN₆ (M+H)⁺: m/z=413.2;Found 413.2.

Example 59.5-(2-Fluoro-6-methylphenyl)-3-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedure described inExample 57, using piperazine instead of piperidin-3-ol as startingmaterial. LC-MS calculated for C₂₂H₂₂FN₆ (M+H)⁺: m/z=389.2; Found 389.2.

Example 60.1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)phenyl)pyrrolidin-3-ol

This compound was prepared according to the procedure described inExample 57, using pyrrolidin-3-ol instead of piperidin-3-ol as startingmaterial. LC-MS calculated for C₂₂H₂₁FN₅O (M+H)⁺: m/z=390.2; Found390.2.

Intermediate 1. tert-Butyl3,5-difluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzyl(methyl)carbamate

Step 1. tert-Butyl 3,5-difluorobenzyl(methyl)carbamate

To a solution of 3,5-difluorobenzaldehyde (15.0 g, 106 mmol) in MeOH(528 ml) was added methylamine (79.0 ml, 158 mmol, 2M in THF), and thereaction mixture was stirred at r.t. for 1 hour. Sodium borohydride(7.99 g, 211 mmol) was added and the reaction was stirred until bubblinghas stopped. The mixture was concentrated to dryness, and then dissolvedin 300 mL of DCM. Sodium bicarbonate aq. solution was added and thereaction mixture was stirred at r.t. for another 1 hour. The organiclayer was dried over MgSO₄, filtered and concentrated to dryness. Theresidue was dissolved in DCM (528 ml), then DIPEA (18.4 ml, 106 mmol)and di-tert-butyl dicarbonate (24.5 ml, 106 mmol) were added. Theresulting solution was stirred at r.t. for 1 hour. The solution wasconcentrated to dryness and the residue was purified by silica gelchromatography using 0-70% ethyl acetate in hexanes to afford desiredproduct as colorless oil (15.1 g, 55.4%). LC-MS calculated forC₉H₁₀F₂NO₂ (M+2H-tBu)⁺: m/z=202.1; Found 202.2.

Step 2. tert-Butyl5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2,6-difluorophenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate

To a solution of tert-butyl (3,5-difluorobenzyl)(methyl)carbamate (6.67g, 25.9 mmol) in THF (120 ml) was added n-butyllithium (13.8 ml, 34.6mmol) dropwise at −78° C. and the reaction was stirred at −78° C. for 1hour. After this time2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (8.04 g, 43.2 mmol)was added and it was allowed to warm up to r.t. over 1 hour. Thereaction mixture was quenched with water and the desired product wasextracted with ethyl acetate. The organic layer was washed with brine,dried over MgSO₄, filtered and then concentrated to dryness. The residuewas dissolved in dioxane (40 ml) and water (10.00 ml). To the resultingsolution was added tert-butyl5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (2.2 g, 8.64 mmol)and potassium phosphate, tribasic (3.01 g, 17.3 mmol). The reaction wasdegassed andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (0.680 g, 0.864 mmol) was added. The solution was thenstirred at 60° C. for 1 hour. After cooling to r.t. solvents wereevaporated in vacuo and the residue was purified by silica gelchromatography using 0-10% methanol in DCM to afford desired product asyellowish oil (1.70 g, 41.4%). LC-MS calculated for C₂₃H₂₈F₂N₅O₄ (M+H)⁺:m/z=476.2; found 476.2.

Step 3. tert-Butyl3,5-difluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzyl(methyl)carbamate

To a solution of tert-butyl5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2,6-difluorophenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(1.60 g, 3.36 mmol) in dioxane (16.8 ml) and water (16.8 ml) was addedpotassium carbonate (2.3 g, 16.8 mmol) and the reaction was stirred at80° C. for 2 hours. It was then cooled to r.t., diluted with DCM, washedwith water, sodium bicarbonate aq. solution and brine. The organic layerwas dried over MgSO₄, filtered and then concentrated to dryness. Theresidue was dissolved in acetonitrile (33.6 ml). To the resultingsolution was added N-iodosuccinimide (643 mg, 2.86 mmol) and thereaction was stirred at 50° C. for 1 hour. After this time it was cooledto r.t. then DIPEA (588 μl, 3.36 mmol) was added followed by addition ofSEM-Cl (507 μl, 2.86 mmol) dropwise. The resulting solution was stirredfor 30 mins at r.t. then concentrated to dryness. The residue waspurified by silica gel chromatography using 0-70% ethyl acetate inhexanes to afford Intermediate 1 as dark brownish solid (260 mg, 12.2%).LC-MS calculated for C₂₄H₃₃F₂IN₅O₃Si (M+H)⁺: m/z=632.2; found 632.2.

Example 61.5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N-methylpicolinamide

To a solution of Intermediate I (20 mg, 0.032 mmol) in dioxane (1 mL)and water (0.250 mL) was added potassium phosphate, tribasic (13 mg,0.063 mmol)and/V-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide(16 mg, 0.063 mmol). The mixture was degassed andchloro(2-dicycloheylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (4.98 mg, 6.33 μmol) was added. The resulting mixture wasstirred at 90° C. for 2 hours. The mixture was filtered, and 4.0 M HClsolution in dioxane (1 mL, 4.000 mmol) and 1 mL of water were added andthe reaction mixture was stirred for another 1 hour at 80° C. 1 mL ofmethanol was added and the reaction mixture was stirred for another 30mins at 80° C. The mixture was then diluted with acetonitrile, filteredand purified by prep-LCMS (XBridge C18 column, eluting with a gradientof acetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LC-MS calculated for C₂₀H₁₈F₂N₇O (M+H)⁺: m/z=410.2; found 410.2.

Example 62.4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-2-fluoro-N-methylbenzamide

This compound was prepared according to the procedure described inExample 61, using2-fluoro-N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamideinstead ofN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide asstarting material. LC-MS calculated for C₂₁H₁₈F₃N₆O (M+H)⁺: m/z=427.2;Found 427.2.

Example 63.1-(3,5-Difluoro-4-(3-(4-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedure described inExample 61, using2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane insteadof/V-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamideas starting material. LC-MS calculated for C₂₀H₁₈F₂N₅O (M+H)⁺:m/z=382.2; Found 382.2.

Example 64.3-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)benzonitrile

This compound was prepared according to the procedure described inExample 61, using3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile insteadof/V-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamideas starting material. LC-MS calculated for C₂₀H₅F2N6 (M+H)⁺: m/z=377.2;Found 377.2.

Example 65.1-(3,5-Difluoro-4-(3-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedure described inExample 61, using tert-butyl4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine-1-carboxylateinstead ofN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide asstarting material. LC-MS calculated for C₂₄H₂₅F₂N₆ (M+H)⁺: m/z=435.2;Found 435.2.

Example 66.1-(3,5-Difluoro-4-(3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedure described inExample 61, using4,4,5,5-tetramethyl-2-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1,3,2-dioxaborolaneinstead ofN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide asstarting material. LC-MS calculated for C₂₄H₂₄F₂N₅O (M+H)⁺: m/z=436.2;Found 436.2.

Example 67.1-(4-(3-(4-(4-Ethylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)-3,5-difluorophenyl)-N-methylmethanamine

This compound was prepared according to the procedure described inExample 61, using1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazineinstead ofN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide asstarting material. LC-MS calculated for C₂₅H₂₈F₂N₇ (M+H)⁺: m/z=464.2;Found 464.2. ¹H NMR (500 MHz, DMSO) δ 9.95 (s, 1H), 9.51 (s, 1H), 9.19(s, 1H), 8.33 (d, J=8.8 Hz, 2H), 7.46 (d, J=8.2 Hz, 2H), 7.20 (d, J=9.0Hz, 2H), 4.28 (s, 2H), 3.98 (d, J=12.4 Hz, 2H), 3.61 (d, J=9.8 Hz, 3H),3.22 (q, J=7.3 Hz, 2H), 3.18-3.02 (m, 3H), 2.66 (s, 3H), 1.27 (t, J=12Hz, 3H).

Example 68.5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-2-morpholinonicotinonitrile

This compound was prepared according to the procedure described inExample 61, using2-morpholino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrileinstead ofN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide asstarting material. LC-MS calculated for C₂₃H₂₁F₂N₈O (M+H)⁺: m/z=463.2;Found 463.2.

Example 69.1-(3,5-Difluoro-4-(3-(3-fluoro-2-morpholinopyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedure described inExample 61, using4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholineinstead ofN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamide asstarting material. LC-MS calculated for C₂₂H₂₁F₃N₇O (M+H)⁺: m/z=456.2;Found 456.2.

Example 70.1-(4-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol

Step 1. tert-Butyl4-(3-(6-chloropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,5-difluorobenzyl(methyl)carbamate

To a solution of Intermediate 1 (500 mg, 0.792 mmol) in dioxane (6 ml)and water (1.5 ml) was added (6-chloropyridin-3-yl)boronic acid (112 mg,0.713 mmol) followed by addition of potassium phosphate, tribasic (336mg, 1.58 mmol). The resulting solution was degassed, PdCl₂(dppf) (64 mg,0.079 mmol) was added and the reaction mixture was stirred at 90° C. for2 hours. The reaction mixture was cooled to r.t. and concentrated todryness. The residue was purified by silica gel chromatography using0-100% ethyl acetate in hexanes to afford desired product as brownishoil (310 mg, 63.4%). LC-MS calculated for C₂₉H₃₆ClF₂N₆O₃Si (M+H)⁺:m/z=618.2; found 618.2.

Step 2.1-(4-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol

To a solution of tert-butyl(4-(3-(6-chloropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,5-difluorobenzyl)(methyl)carbamate(100 mg, 0.162 mmol) in dioxane (5 mL) was added cesium carbonate (106mg, 0.324 mmol) and 2-methyl-1-(piperazin-1-yl)propan-2-ol (128 mg,0.810 mmol). The resulting mixture was degassed andchloro(2-dicyclohexylphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(12 mg, 0.016 mmol) was added. The resulting mixture was stirred at 90°C. for 2 hours. The reaction mixture was filtered, and 4.0 M HClsolution in dioxane (1 mL, 4.0 mmol) and 1 mL of water were added. Theresulting mixture was stirred for another 1 hour at 80° C. 1 mL ofmethanol was added and the reaction mixture was stirred for another 30mins at 80° C. The solution was then diluted with acetonitrile, filteredand then purified by prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min). LC-MS calculated for C₂₆H₃₁F₂N₈O (M+H)⁺: m/z=509.2; found509.2. ¹H NMR (600 MHz, DMSO) δ 9.54 (s, 1H), 9.22 (d, J=2.3 Hz, 1H),9.08 (bs, 1H), 8.50 (dd, J=8.9, 2.4 Hz, 1H), 7.46 (d, J=8.0 Hz, 2H),7.14 (d, J=8.9 Hz, 1H), 4.31 (d, J=18.8 Hz, 2H), 4.28 (t, J=5.6 Hz, 2H),3.71-3.61 (m, 2H), 3.59-3.49 (m, 2H), 3.30-3.21 (m, 2H), 3.20 (s, 2H),2.65 (t, J=5.1 Hz, 3H), 1.29 (s, 6H).

Example 71.(1-(5-(5-(2,6-Difluoro-4-((methylainino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)-3-methylpiperidin-3-yl)methanol

This compound was prepared according to the procedure described inExample 70, using (3-methylpiperidin-3-yl)methanol instead of2-methyl-1-(piperazin-1-yl)propan-2-ol as starting material. LC-MScalculated for C₂₅H₂₈F₂N₇O (M+H)⁺: m/z=480.2; Found 480.2.

Example 72.7V-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)-1-(methylsulfonyl)piperidin-4-amine

Step 1. tert-Butyl4-(3-(4-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,5-difluorobenzyl(methyl)carbamate

To a solution of Intermediate 1 (1 g, 1.583 mmol) in dioxane (12 ml) andwater (3 ml) was added (4-chlorophenyl)boronic acid (173 mg, 1.11 mmol)followed by addition of potassium phosphate, tribasic (672 mg, 3.17mmol). The resulting solution was degassed, PdCl₂(dppf) (129 mg, 0.158mmol) was added and the reaction mixture was stirred at 90° C. for 2hours. The mixture was cooled to r.t. and then concentrated to dryness.The residue was purified by silica gel chromatography using 0-100% ethylacetate in hexanes to afford desired product as brownish oil (450 mg,46.1%). LC-MS calculated for C₃₀H₃₇ClF₂N₅O₃Si (M+H)⁺: m/z=616.2; found616.2.

Step 2.N-(4-(5-(2,6-Difluoro-4-(trimethylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)-1-(methylsulfonyl)piperidin-4-amine

To a solution of tert-butyl(4-(3-(4-chlorophenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,5-difluorobenzyl)(methyl)carbamate(30 mg, 0.049 mmol) in dioxane (1 ml) was added cesium carbonate (79 mg,0.24 mmol) and 1-(methylsulfonyl)piperidin-4-amine (43.4 mg, 0.243mmol). The mixture was degassed andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (7.66 mg, 9.74 μmol) was added. The resulting mixture wasstirred at 90° C. for 2 hours. The mixture was filtered, and 4.0 M HClsolution in dioxane (1 mL, 4.0 mmol) and 1 mL of water were added. Thereaction was stirred for another 1 hour at 80° C. 1 mL of methanol wasadded, and the reaction mixture was stirred for another 30 mins at 80°C. The solution was then diluted with acetonitrile, filtered and thenpurified by prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LC-MS calculated for C₂₅H₂₈F₂N₇O₂S (M+H)⁺: m/z=528.2; found 528.2.

Example 73.2-(4-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)piperazin-1-yl)ethanol

This compound was prepared according to the procedure described inExample 72, using 2-(piperazin-1-yl)ethanol instead of1-(methylsulfonyl)piperidin-4-amine as starting material. LC-MScalculated for C₂₅H₂₈F₂N₇O (M+H)⁺: m/z=480.2; Found 480.2. ¹H NMR (400MHz, DMSO) δ 9.78 (s, 1H), 9.50 (s, 1H), 9.10 (s, 1H), 8.30 (d, J=8.5Hz, 2H), 7.53-7.38 (m, 2H), 7.23-7.12 (m, 2H), 4.27 (s, 2H), 3.94 (d,J=12.4 Hz, 2H), 3.79 (t, J=5.2 Hz, 2H), 3.68-3.56 (m, 3H), 3.27 (t,J=4.9 Hz, 2H), 3.23-3.12 (m, 3H), 2.66 (s, 3H).

Example 74.1-(3,5-Difluoro-4-(3-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine

Step 1. tert-Butyl3,5-difluoro-4-(3-(6-(piperazin-1-yl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzyl(methyl)carbamate

To a solution of tert-butyl(3,5-difluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzyl)(methyl)carbamate(Intermediate 1, 300 mg, 0.475 mmol) in dioxane (3 mL) and water (0.750mL) was added potassium phosphate, tribasic (202 mg, 0.950 mmol) and1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(165 mg, 0.570 mmol). The resulting mixture was degassed andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (74 mg, 0.095 mmol) was added. The resulting mixture wasstirred at 90° C. for 2 hours. The mixture was concentrated to dryness.The residue was purified by silica gel chromatography using 0-10%methanol in DCM to afford desired product as brownish oil (220 mg,69.5%). LC-MS calculated for C₃₃H₄₅F₂N₈O₃Si (M+H)⁺: m/z=667.2; found667.2.

Step 2.1-(3,5-Difluoro-4-(3-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine

To a solution of tert-butyl(3,5-difluoro-4-(3-(6-(piperazin-1-yl)pyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzyl)(methyl)carbamate(25 mg, 0.037 mmol) in DCM (750 μl) was added DIPEA (32.7 μl, 0.187mmol) followed by addition of methanesulfonyl chloride (22 mg, 0.19mmol). The resulting solution was stirred at r.t. for 1 hour. 1 mL ofTFA was added, and the reaction mixture was stirred at r.t. for another1 hour. The solvent was then removed, and the residue was dissolved inmethanol and stirred at 60° C. for 15 mins. The solution was dilutedwith acetonitrile, filtered and then purified by prep-LCMS (XBridge C18column, eluting with a gradient of acetonitrile/water containing 0.1%TFA, at flow rate of 60 mL/min). LC-MS calculated for C₂₃H25F₂N802S(M+H)⁺: m/z=515.2; found 515.2.

Example 75.4-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)-N-ethyl-N-methylpiperazine-1-carboxamide

This compound was prepared according to the procedure described inExample 74, using ethyl(methyl)carbamic chloride instead ofmethanesulfonyl chloride as starting material. LC-MS calculated forC₂₆H₃₀F₂N₉O (M+H)⁺: m/z=522.2; Found 522.2.

Example 76.1-(3-Fluoro-4-(3-(6-(piperidin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine

Step 1. tert-Butyl 3-fluoro-5-(trifluoromethyl)benzyl(methyl)carbamate

To a solution of 3-fluoro-5-(trifluoromethyl)benzaldehyde (20.0 g, 104mmol) in MeOH (500 ml) was added methylamine solution (104 ml, 208 mmol,2M in THF) and the reaction mixture was stirred at r.t. for 1 hour.Sodium borohydride (7.88 g, 208 mmol) was added, and the reactionmixture was stirred for additional 30 mins. The mixture was concentratedto dryness and 300 mL of DCM was added. Aqueous solution of sodiumbicarbonate was added, and the reaction mixture was stirred at r.t. foranother 1 hour. The organic layer was separated, and it was dried overMgSO₄, filtered and concentrated to dryness. To a solution of theresulting residue in DCM (521 ml) was added triethylamine (14.5 ml, 104mmol) and di-tert-butyl dicarbonate (22.7 g, 104 mmol). The resultingsolution was stirred at r.t. for 1 hour. After this time it wasconcentrated to dryness and the residue was purified by silica gelchromatography using 0-70% ethyl acetate in hexanes to afford desiredproduct as colorless oil (15.1 g, 47.0%). LC-MS calculated forC₁₀H₁₀F₄NO₂ (M+H—C₄H₈)⁺: 252.1; found 252.2.

Step 2. tert-Butyl5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate

To a solution of tert-butyl(3-fluoro-5-(trifluoromethyl)benzyl)(methyl)carbamate (2.3 g, 7.5 mmol)in THF (33.3 ml) was added n-butyllithium (8.98 ml, 22.5 mmol) dropwiseat −78° C., and the reaction mixture was stirred at −78° C. for 1 hour.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.57 g, 29.9 mmol)was added. The resulting mixture was allowed to warm up to r.t. over 1hour. The resulting solution was quenched with water, neutralized topH=6, and the desired product was extracted with ethyl acetate. Theorganic layer was washed with brine, dried over MgSO₄, filtered and thenconcentrated to dryness. To a solution of the resulting residue indioxane (33.3 ml) and water (8.32 ml) was added potassium phosphate(1.30 g, 7.48 mmol) and tert-butyl5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (0.953 g, 3.74mmol). The mixture was degassed withN₂,chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (0.118 g, 0.150 mmol) was added, and the reaction mixturewas stirred at 60° C. for 1 hour. After this time it was concentrated todryness. The residue was purified by silica gel chromatography using0-100% ethyl acetate in hexanes to afford desired product as yellowishoil (850 mg, 43.2%). LC-MS calculated for C₂₄H₂₈F₄N₅O₄ (M+H)⁺:m/z=526.2; Found 526.2.

Step 3. tert-Butyl3-fluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)benzyl(methyl)carbamate

To a solution of tert-butyl5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-(7]pyrimidine-1-carboxylate(250 mg, 0.476 mmol) in dioxane (2.5 ml) and water (2.5 ml) was addedpotassium carbonate (329 mg, 2.38 mmol), and the reaction mixture wasstirred at 80° C. for 2 hours. The mixture was cooled to r.t., dilutedwith DCM and washed with water, sodium bicarbonate and brine. Theorganic layer was dried over MgSO₄, filtered and then concentrated todryness. To a solution of the resulting residue in acetonitrile (5 ml)was added A-iodosuccinimide (91 mg, 0.40 mmol) and the reaction wasstirred at 50° C. for 1 hour. The mixture was cooled to r.t., DIPEA (83μl, 0.476 mmol) was added followed by the dropwise addition of SEM-Cl(71.7 μl, 0.404 mmol). The resulting solution was stirred at r.t. for 30mins, then concentrated to dryness. The residue was purified by silicagel chromatography using 0-70% ethyl acetate in hexanes to afforddesired product as dark brownish solid (260 mg, 80.0%). LC-MS calculatedfor C₂₅H₃₃F₄IN₅O₃Si (M+H)+: m/z=682.2; found 682.2.

Step 4.1-(3-Fluoro-4-(3-(6-(piperidin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine

To a solution of tert-butyl(3-fluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)benzyl)(methyl)carbamate(20 mg, 0.029 mmol) in dioxane (800 μl) and water (200 μl) was added(6-(piperidin-1-yl)pyridin-3-yl)boronic acid (6.1 mg, 0.029 mmol)followed by the addition of potassium phosphate, tribasic (12.4 mg,0.058 mmol). The resulting solution was degassed, PdCl₂(dppf) (2.4 mg,2.93 μmol) was added, and the reaction mixture was stirred at 90° C. for2 hours. The mixture was cooled to r.t. and then HCl, 4.0 M in dioxane(1 ml, 4.00 mmol) was added, followed by the addition of 1 ml of water.The resulting solution was stirred at 80° C. for 2 hours. The solutionwas cooled to r.t., diluted with acetonitrile, filtered and purified byprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min).LC-MS calculated for C₂₄H24F₄N₇ (M+H)⁺: m/z=486.2; found 486.2.

Example 77.1-(4-(5-(5-(2-Fluoro-4-((methylamino)methyl)-6-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3d]pyrimidin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone

This compound was prepared according to the procedure described inExample 76, using 6-(4-acetylpiperazin-1-yl)pyridin-3-ylboronic acidinstead of (6-(piperidin-1-yl)pyridin-3-yl)boronic acid as startingmaterial. LC-MS calculated for C₂₅H₂₅F₄N80 (M+H)⁺: m/z=529.2; Found529.2.

Example 78.1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine

Step 1. tert-Butyl 5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate

In a 50 mL round-bottom flask with a stir bar,5-chloro-1H-pyrazolo[4,3-d]pyrimidine (Oxchem, 600 mg, 3.88 mmol) andtriethylamine (649 μl, 4.66 mmol) were dissolved in CH₂Cl₂ (12.9 mL).Di-tert-butyl dicarbonate (991 μl, 4.27 mmol) was added, and thereaction mixture was stirred at r.t. for 1 h. The reaction mixture wasthen diluted with water, extracted with CH₂Cl₂, and the combined organiclayers were dried over magnesium sulfate and concentrated under reducedpressure. The crude product was purified by Biotage Isolera™ (860 mg,87%). LCMS calculated for C₁₀H₁₂ClN₄O₂ (M+H)⁺ m/z=255.1; found 255.2.

Step 2. 4-Bromo-3-fluoro-5-methylaniline

N-Bromosuccinimide (15.8 g, 89 mmol) was added to a solution of3-fluoro-5-methylaniline (Combi-Blocks, 11 g, 88 mmol) in DMF (80 mL)cooled to 0° C. in an ice bath. The reaction mixture was stirred at 0°C. for 30 minutes. After warming to r.t., the reaction was stirred foran additional 1 hour. Water and EtOAc were then added, and the organicphase was washed with saturated aqueous NaHCO₃ and brine. The organicphase was then dried over magnesium sulfate and the solvents wereevaporated under reduced pressure. The crude product was purified byBiotage Isolera™ (17.2 g, 96%). LCMS calculated for C₇H₈BrFN (M+H)⁺m/z=203.9; found 204.0.

Step 3. 2-Bromo-1-fluoro-5-iodo-3-methylbenzene

To a solution of 4-bromo-3-fluoro-5-methylaniline (7.28 g, 36 mmol) inacetonitrile (190 mL) cooled to 0° C. in an ice bath was added sulfuricacid (4.75 mL, 89 mmol) dissolved in H₂O (10 mL). After stirring for 5minutes, a solution of sodium nitrite (4.92 g, 71.4 mmol) in water (10mL) was added dropwise, and the reaction mixture was stirred for anadditional 15 minutes at 0° C. Potassium iodide (23.7 g, 143 mmol) inwater (20 mL) was then added, and the ice-bath was removed. Afterwarming to r.t., the reaction was stirred for an additional 20 minutesbefore the reaction was quenched via the addition of aqueous Na₂S₂O₃.The mixture was then extracted with ethyl acetate and the combinedorganic phases were washed with brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The crude product was purified byBiotage Isolera™ (10.3 g, 94%). ¹H NMR (400 MHz, CDCl₃) δ 7.39 (br s,1H), 7.29 (m, 1H), 2.38 (s, 3H) ppm.

Step 4. 2-Bromo-1-fluoro-3-methyl-5-vinylbenzene

To a solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene (10.3 g, 32.8mmol) in 1,4-dioxane (80 mL) and water (13.3 mL) was added4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (Aldrich, 6.16 mL, 34.5mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl₂) (2.40 g, 3.3 mmol), and potassium phosphate tribasic (13.9g, 65.7 mmol). The reaction mixture was degassed with nitrogen andheated to 70° C. for 1 h. After cooling to r.t., the reaction wasfiltered over a pad of Celite, diluted with water, and extracted withethyl acetate. The combined organic phases were washed with brine, driedover magnesium sulfate, and concentrated under reduced pressure. Thecrude product was purified by Biotage Isolera™ (5.46 g, 77%). ¹H NMR(400 MHz, CDCl₃) δ 7.05 (br s, 1H), 7.01 (dd, J=2.0, 9.4 Hz, 1H), 6.60(dd, J=10.9, 17.5 Hz, 1H), 5.75 (d, J=17.5 Hz, 1H), 5.31 (d, J=10.9 Hz,1H), 2.42 (s, 3H) ppm.

Step 5. 4-Bromo-3-fluoro-5-methylbenzaldehyde

To a solution of 2-bromo-1-fluoro-3-methyl-5-vinylbenzene (5.46 g, 25.4mmol) in acetone (46 mL) and water (4.6 mL) was sequentially addedsodium periodate (21.7 g, 102 mmol) and a 4% aqueous solution of osmiumtetroxide (8.07 mL, 1.27 mmol). The reaction was stirred at r.t. for 2h. The reaction mixture was then filtered over a pad of celite, dilutedwith water, and extracted with ethyl acetate. The combined organicphases were washed with brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The crude product was purified byBiotage Isolera™ (3.22 g, 58%). ¹H NMR (400 MHz, CDCl₃) δ 9.93 (d, J=1.8Hz, 1H), 7.55 (d, J=1.8 Hz, 1H), 7.44 (dd, J=1.8, 7.8 Hz, 1H), 2.52 (s,3H) ppm.

Step 6. 1-(4-Bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine

In a 20 mL scintillation vial equipped with a magnetic stir bar,4-bromo-3-fluoro-5-methylbenzaldehyde (1.46 g, 6.70 mmol) was dissolvedin MeOH (6.70 mL) and the reaction was placed under a nitrogenenvironment. Following this, a 33% solution of methanamine (3.15 g, 33.5mmol) in ethanol and titanium(IV) isopropoxide (0.982 mL, 3.35 mmol)were added, and the reaction mixture was stirred at r.t. for 3 hours.Sodium borohydride (1.01 g, 26.8 mmol) was then added to the reactionmixture portion wise and stirring was continued at r.t. for anadditional 1.5 hours. NH₄OH (30% aqueous solution) was added to thereaction mixture and stirring continued for another 15 minutes. Thereaction was then acidified with 1 N HCl and extracted with ethylacetate. The water layer was then made basic and extracted with ethylacetate. The combined organic phases were washed with brine, dried overmagnesium sulfate, and concentrated under reduced pressure to afford1-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine (1.32 g, 85%) asa light yellow oil. The crude product was used in the next step withoutfurther purification. LCMS calculated for C₉H₁₂BrFN (M+H)⁺ m/z=232.0;found 231.9.

Step 7. tert-Butyl 4-bromo-3-fluoro-5-methylbenzyl(methyl)carbamate

To a solution of 1-(4-bromo-3-fluoro-5-methylphenyl)-N-methylmethanamine(1.32 g, 5.67 mmol) and triethylamine (1.58 mL, 11.34 mmol) in THF (18.9mL) was added di-tert-butyl dicarbonate (1.58 mL, 6.80 mmol). Thereaction mixture was then stirred at ambient temperature for 1 hour. Thereaction mixture was then diluted with water and extracted with ethylacetate. The combined organic layers were then dried with magnesiumsulfate and concentrated under reduced pressure. The crude product waspurified by Biotage Isolera™ (1.42 g, 78%). LCMS calculated forC₁₀H₁₂BrFNO₂ (M+H—C₄H₈)⁺ m/z=276.0; found 276.0.

Step 8. tert-Butyl3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate

In an oven-dried 20 mL scintillation vial with a stir bar, tert-butyl(4-bromo-3-fluoro-5-methylbenzyl)(methyl)carbamate (573 mg, 1.73 mmol)was dissolved in THF (11.5 mL). The reaction mixture was then cooled to−78° C. in a dry ice/acetone bath and n-BuLi (1.6 M solution in hexanes,1.19 mL, 1.90 mmol) was added dropwise. The reaction mixture was thenallowed to stir for 3 minutes before2-isopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (427 μL, 2.25 mmol)was added dropwise. The mixture was warmed to r.t and stirred for anadditional 5 hours. The reaction mixture was quenched by the addition ofwater, acidified to pH 5-6 using 1 N HCl, and extracted with ethylacetate. The combined organic layers were then washed with brine, driedover magnesium sulfate, and concentrated to afford tert-butyl3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl(methyl)carbamate.The crude product was used in the next step without furtherpurification. LCMS calculated for C₁₆H24BrFNO₄ (M+H—C₄H₈)⁺ m/z=324.2;found 324.1.

Step 9. tert-Butyl5-(4-((tert-butoxycarbonyl(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate

In a 20 mL scintillation vial equipped with a magnetic stir bar,tert-butyl 5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (340 mg,1.34 mmol) and tert-butyl(3-fluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)(methyl)carbamate(557 mg, 1.47 mmol) were dissolved in 1,4-dioxane (8.0 mL) and water(2.0 mL). To this mixture was addedchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (158 mg, 0.20 mmol) and potassium phosphate tribasic (567mg, 2.67 mmol). The reaction mixture was then degassed by bubblingnitrogen through the resulting mixture, and the reaction mixture wassealed and heated to 75° C. for 1 h. After cooling to r.t., the reactionwas diluted with water and extracted with ethyl acetate. The combinedorganic layers were washed with brine, dried over magnesium sulfate, andconcentrated under reduced pressure. The crude product was purified byBiotage Isolera™ (532 mg, 84%). LCMS calculated for C₂₄H₃₁FN₅O₄ (M+H)⁺m/z=472.2; found 472.3.

Step 10. tert-Butyl3-fluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-methylbenzyl(methyl)carbamate

In a 20 mL scintillation vial with a stir bar, tert-butyl5-(4-(((tert-butoxycarbonyl)(methyl)amino)methyl)-2-fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(817 mg, 1.73 mmol) and potassium carbonate (958 mg, 6.93 mmol) weredissolved in 1,4-dioxane (6.06 mL) and water (6.06 mL). The reaction wasthen purged under a nitrogen environment and heated to 80° C. for 2hours. The reaction was diluted with water and extracted with ethylacetate. The combined organic phases were then washed with brine, driedover magnesium sulfate, and concentrated. The crude intermediate wasdissolved in acetonitrile (10 mL) and N-iodosuccinimide (507 mg, 2.25mmol) was added, and the reaction mixture heated to 60° C. for 1 hour.N,N-diisopropylethylamine (393 μl, 2.25 mmol) and[2-(trimethylsilyl)ethoxy]methyl chloride (369 μL, 2.08 mmol) were addedto the reaction mixture was stirred at r.t for an additional 1 h. Thereaction mixture was then concentrated under reduced pressure and thecrude product was purified by Biotage Isolera™ (412 mg, 38%). LCMScalculated for C₂₅H₃₆FIN₅O₃Si (M+H)⁺ m/z=628.2; found 628.1.

Step 11.1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine

In a 4 dram vial equipped with a magnetic stir bar, tert-butyl(3-fluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-methylbenzyl)(methyl)carbamate(20 mg, 0.032 mmol) was dissolved in 1,4-dioxane (0.5 mL) and water(0.08 mL). To this solution was added1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(9.28 mg, 0.045 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(Pd XPhos G2) (2.5 mg, 0.0032 mmol), and potassium phosphate (13.5 mg,0.064 mmol). The reaction mixture was then degassed, sealed, and stirredat 85° C. for 1 h. The reaction was then concentrated and CH₂Cl₂ (0.25mL) followed by TFA (0.25 mL) were added, and the mixture was stirred at30° C. for 90 minutes. The reaction was then concentrated and methanol(1.0 mL) followed by 7 drops of NH₄OH (30% aqueous solution) was addedand stirring was continued at 30° C. for 1 hour. The reaction mixturewas then concentrated, dissolved in methanol and purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₁₈H₁₉FN₇ (M+H)⁺: m/z=352.2; Found: 352.2.

Example 79.2-(4-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-1H-pyrazol-1-yl)benzonitrile

In a 4 dram vial equipped with a magnetic stir bar, tert-butyl(3-fluoro-4-(3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-methylbenzyl)(methyl)carbamate(18.9 mg, 0.030 mmol) was dissolved in 1,4-dioxane (0.5 mL) and water(0.08 mL). To this solution was added2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)benzonitrile(12.4 mg, 0.042 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (Pd XPhos G2) (3.6 mg, 0.0032mmol), and potassium phosphate (16.0 mg, 0.064 mmol). The reactionmixture was then degassed, sealed, and stirred at 80° C. for 1 h.Following this, a 4 N solution of HCl in 1,4-dioxane (2 mL) was addedand the reaction was stirred at r.t. for 1 hour. The reaction mixturewas then concentrated, dissolved in methanol and purified with prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min). LCMS calculated forC₂₄H₂₀FN₈ (M+H)⁺: m/z=439.2; Found: 439.1.

Example 80.5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

Step 1. tert-Butyl4-(4-bromo-3-fluoro-5-methylphenyl)-4-oxobutylcarbamate

To a solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene (1.34 g, 4.25mmol, Example 78, Step 3) in THF (30 mL) was added a solution ofisopropylmagnesium chloride in THF (2.13 mL, 4.25 mmol, 2 M) dropwise at−40° C. After stirring at −40° C. for 1 h, the mixture was cooled to−78° C. and tert-butyl 2-oxopyrrolidine-1-carboxylate (0.726 mL, 4.25mmol) was added. The mixture was then slowly warmed to RT over 1.5 h.The mixture was quenched by 1 M HCl, extracted with ethyl acetate andconcentrated in vacuo. The obtained crude product was purified byBiotage Isolera™ to give the desired product. LCMS calculated forC₁₁H₁₄BrFNO (M-Boc+2H)⁺: m/z=274.0; Found: 274.0.

Step 2. tert-Butyl2-(4-bromo-3-fluoro-5-methylphenyl)pyrrolidine-1-carboxylate

To a solution of tert-butyl4-(4-bromo-3-fluoro-5-methylphenyl)-4-oxobutylcarbamate (1.30 g, 3.47mmol) in DCM (15 mL) was added 15 mL TFA, and the mixture was stirred atRT for 30 min. The mixture was concentrated in vacuo and then dissolvedin 30 mL THF. To this solution was added triethylamine (0.593 mL, 4.25mmol) and sodium triacetoxyborohydride (1.80 g, 8.51 mmol). The mixturewas stirred at RT for 18 h and then quenched by 1 M NaOH. The mixturewas extracted by ethyl acetate and concentrated in vacuo. The obtainedcrude product was dissolved in THF (20 mL). To this solution was addeddi-tert-butyl dicarbonate (1.86 g, 8.51 mmol) and triethylamine (0.513mL, 3.68 mmol) at RT. After stirring for 1 h, the solvents wereevaporated under reduced pressure and the obtained crude product waspurified by Biotage Isolera™ to give the desired product. LCMScalculated for C₁₂H₁₄BrFNO₂ (M-C₄H₈+H)⁺: m/z=302.0; Found: 302.0.

Step 3.5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

A mixture of tert-butyl2-(4-bromo-3-fluoro-5-methylphenyl)pyrrolidine-1-carboxylate (65 mg,0.181 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(69.1 mg, 0.272 mmol), potassium acetate (53.4 mg, 0.544 mmol) and(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complexwith dichloromethane (1:1) (29.6 mg, 0.036 mmol) in dioxane (10 mL) wasstirred at 110° C. for 24 h. After cooling to room temperature, themixture was concentrated in vacuo. A mixture of this crude material,5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoy)methyl)-1H-pyrazolo[4,3-d]pyrimidine(25.8 mg, 0.056 mmol, Example 1, Step 3), XPhos Pd G2 (4.14 mg, 5.61μmol) and cesium carbonate (54.9 mg, 0.168 mmol) in dioxane (10 mL) andwater (2 mL) was stirred at 70° C. for 18 h. After cooling to roomtemperature, the mixture was concentrated in vacuo. The crude mixturewas then dissolved in DCM (2.0 mL) and TFA (2.0 mL) was added dropwiseat room temperature. After stirring for 2 h, the mixture wasconcentrated in vacuo. The crude mixture was dissolved in MeOH (3.5 mL)and 10% aqueous NH₄OH (1.5 mL) was added. The mixture was purified withprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) togive the desired product. LCMS calculated for C₂₇H₃₁FN₇ (M+H)⁺:m/z=472.3; Found: 472.3.

Example 81.5-(2-Fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

Step 1. tert-Butyl6-(4-bromo-3-fluoro-5-methylphenyl)-3,4-dihydropyridine-1(2H)-carboxylate

A solution of 2-bromo-1-fluoro-5-iodo-3-methylbenzene (526 mg, 1.67mmol, Example 78, Step 3), tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (516 mg, 1.67 mmol),(1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complexwith dichloromethane (1:1) (136 mg, 0.167 mmol) and potassium carbonate(461 mg, 3.34 mmol) in dioxane (10 mL) and water (2 mL) was stirred at65° C. for 18 h. After cooling to room temperature, the mixture wasconcentrated in vacuo. The obtained crude product was purified byBiotage Isolera™ to give the desired product. LCMS calculated forC₁₃H₁₄BrFNO₂ (M-C₄H8+H)⁺: m/z=314.0; Found: 313.9.

Step 2. tert-Butyl2-(4-bromo-3-fluoro-5-methylphenyl)piperidine-1-carboxylate

To a solution of tert-butyl6-(4-bromo-3-fluoro-5-methylphenyl)-3,4-dihydropyridine-1(2H)-carboxylate(530 mg, 1.42 mmol) in DCM (10 mL) was added 10 mL TFA, and the mixturewas stirred at RT for 30 min. The mixture was concentrated in vacuo andthen dissolved in 20 mL THF. To this solution was added triethylamine(0.233 mL, 1.67 mmol) and sodium triacetoxyborohydride (707 mg, 3.34mmol). The mixture was stirred at RT for 18 h and then quenched by 1 MNaOH. The mixture was extracted by ethyl acetate and concentrated invacuo. The obtained crude product was dissolved in THF (20 mL). To thissolution was added di-tert-butyl dicarbonate (364 mg, 1.67 mmol) at RT.After stirring for 3 h, the solvents were evaporated under reducedpressure and the obtained crude product was purified by Biotage Isolera™to give the desired product. LCMS calculated for C₁₃H₁₆BrFNO₂(M-C₄H₈+H)⁺: m/z=316.0; Found: 315.9.

Step 3.5-(2-Fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

A mixture of tert-butyl2-(4-bromo-3-fluoro-5-methylphenyl)piperidine-1-carboxylate (65 mg,0.175 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(66.5 mg, 0.262 mmol), potassium acetate (51.4 mg, 0.524 mmol) and(1,1-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) complex withdichloromethane (1:1) (28.5 mg, 0.035 mmol) in dioxane (10 mL) wasstirred at 105° C. for 24 h. After cooling to room temperature, themixture was concentrated in vacuo. The crude boronic ester intermediatewas treated with5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine(24.9 mg, 0.054 mmol, Example 1, Step 3), XPhos Pd G2 (4.0 mg, 5.43μmol) and cesium carbonate (53.0 mg, 0.163 mmol) in dioxane (10mL)/water (2 mL) and stirred at 70° C. for 18 h. After cooling to roomtemperature, the mixture was concentrated in vacuo. The crude Pdcoupling product mixture was then dissolved in DCM (2.0 mL) and treatedwith TFA (2.0 mL) dropwise at room temperature. After stirring for 2 h,the mixture was concentrated in vacuo. The crude product mixture wasdissolved in MeOH (3.5 mL) and 10% aqueous NH₄OH (1.5 mL) was added. Themixture was purified with prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to give the desired product. LCMS calculated for C₂₈H₃₃FN₇(M+H)⁺: m/z=486.3; Found: 486.4.

Example 82.N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

Step 1.5-Chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine

To a mixture of5-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine(3.25 g, 7.91 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.646 g, 7.91 mmol), dppf-PdCl₂ (0.323 g, 0.396 mmol) and potassiumcarbonate (2.187 g, 15.83 mmol) were added 1,4-dioxane (15.83 ml) andwater (3.96 ml), and the reaction flask was evacuated, back filled withnitrogen, then stirred at 90° C. overnight. The mixture was diluted withDCM and filtered through a pad of Celite. The filtrate was concentratedand purified by Biotage Isolera™ (flash purification system with ethylacetate/hexanes at a ratio from 0 to 100%) to provide the desiredproduct as a dark oil (2.08 g, 72%). LC-MS calculated for C₁₅H₂₂ClN₆OSi[M+H]⁺ m/z: 365.2, found 365.2.

Step 2.3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

To a mixture of 4-bromo-3,5-difluoroaniline (3.30 g, 15.9 mmol),dppf-PdCl₂ (0.648 g, 0.793 mmol), bis(pinacolato)diboron (6.04 g, 23.8mmol) and potassium acetate (3.11 g, 31.7 mmol) was added 1,4-dioxane(31.7 ml) and the reaction flask was evacuated, back filled withnitrogen, then stirred at 100° C. overnight. The reaction mixture wasthen diluted with DCM and filtered through a pad of Celite. The filtratewas concentrated and purified by Biotage Isolera™ (flash purificationsystem with ethyl acetate/hexanes at a ratio from 0 to 100%) to providethe desired product as a brown solid (2.4 g, 59%). LC-MS calculated forC₁₂H₁₇BF₂NO₂ [M+H]⁺ m/z: 256.1, found 256.1.

Step 3. Preparation of3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)aniline

To a mixture of5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine(475 mg, 1.302 mmol),3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (432mg, 1.692 mmol), Xphos Pd G2 (102 mg, 0.130 mmol) and potassiumphosphate, tribasic (553 mg, 2.60 mmol) were added 1,4-dioxane (4.75 ml)and water (0.950 ml) and the reaction mixture was evacuated, back filledwith nitrogen, then stirred at 80° C. for 1 hr. The mixture was thendiluted with DCM and filtered through a plug of Celite. The filtrate wasconcentrated and purified by Biotage Isolera™ (flash purification systemwith dichloromethane/methanol at a ratio from 2 to 10%) to provide thedesired product as a brown solid. LC-MS calculated for C₂₁H₂₆F₂N₇OSi[M+H]⁺ m/z: 458.2, found 458.2.

Step 4. Preparation of2-chloro-N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)acetamide

To a mixture of3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)aniline(100 mg, 0.219 mmol), 2-chloroacetic acid (41.3 mg, 0.437 mmol) and HATU(125 mg, 0.328 mmol) in DMF (1093 μl) was added hunig's base (115 μl,0.656 mmol) and the reaction mixture stirred at r.t. for 1 hr. Themixture was then quenched with water and extracted with ethyl acetate.

The organic layer was washed with water and brine, dried over sodiumsulfate and concentrated. The residue was used in the next step withoutfurther purification. LC-MS calculated for C₂₃H₂₇ClF₂N₇O₂Si [M+H]⁺ m/z:534.2, found 534.2.

Step 5. Preparation ofN-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide

To a solution of2-chloro-N-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)acetamide(25 mg, 0.047 mmol) in DMF (468 μl) was added pyrrolidine (7.83 μl,0.094 mmol) and the reaction mixture was stirred at 80° C. for 2 hrs. Itwas then quenched with water and extracted with ethyl acetate. Theorganic layer was washed with water and brine, dried over sodium sulfateand concentrated. To the residue were added methanol (1 mL) and 4N HCl(1 mL) and the reaction mixture heated to 80° C. for 30 mins, thencooled to r.t., diluted with methanol and purified directly on prep-LCMS(XBridge C18 column, eluting with a gradient of acetonitrile/watercontaining 0.1% TFA, at flow rate of 60 mL/min) to provide the desiredproduct. LC-MS calculated for C₂₁H₂₁F₂N80 [M+H]⁺ m/z: 439.2, found439.2.

Example 83.N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-2-(dimethylamino)acetamide

This compound was prepared using procedures analogous to those forexample 82, with dimethyl amine replacing pyrrolidine. LCMS calculatedfor C₁₉H₁₉F₂N80 [M+H]⁺ m/z: 413.2; Found: 413.2.

Preparation of3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)benzaldehyde

Step 1. Preparation of(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

To a solution of3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde(4.0 g, 14.92 mmol) in tetrahydrofuran (149 ml) was added sodiumborohydride (0.677 g, 17.91 mmol). After 2 hrs, the reaction wasquenched with sat. sodium bicarbonate and extracted with ethyl acetate.The organic layer was washed with brine, dried over sodium sulfate andconcentrated. The crude product was used in the next step withoutfurther purification.

Step 2. Preparation of(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)methanol

To a mixture of5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine(425 mg, 1.165 mmol),(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(472 mg, 1.747 mmol), Xphos Pd G2 (92 mg, 0.116 mmol) and potassiumphosphate (494 mg, 2.329 mmol) were added 1,4-dioxane (3 ml) and water(776 μl), and the reaction flask was evacuated, back filled withnitrogen, then stirred at 95° C. for 2 hrs. The mixture was diluted withDCM and filtered through a pad of Celite. The filtrate was concentratedand purified by Biotage Isolera™ (flash purification system withdichloromethane/methanol at a ratio from 2 to 10%) to provide thedesired product as a dark oil. LCMS calculated for C₂₂H₂₇F₂N₆O₂Si [M+H]⁺m/z: 473.2; Found: 473.2.

Step 3. Preparation of3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzaldehyde

To a solution of(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)methanol(550 mg, 1.164 mmol) in DCM (6 mL) was added manganese dioxide (1.9 g,22.11 mmol). The reaction mixture was heated to 60° C. for 1 hr, andthen filtered through a plug of Celite. The filtrate was concentratedand purified by Biotage Isolera™ (flash purification system withhexanes/ethyl acetate at a ratio from 0 to 100%) to provide the desiredproduct as an oil. LCMS calculated for C₂₂H₂₅F₂N₆O₂Si [M+H]⁺ m/z: 471.2;Found: 471.2.

Example 84.1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine

To a solution of3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzaldehyde(25 mg, 0.053 mmol) and methanamine (2M in THF, 0.133 ml, 0.266 mmol) intoluene (1 ml) was added acetic acid (9.12 μl, 0.159 mmol) and thereaction mixture was stirred at 80° C. overnight. The mixture was thenconcentrated and redissolved in methanol (1 mL). Sodium borohydride(2.010 mg, 0.053 mmol) was then added and the mixture was stirred atr.t. for 30 mins. Then 4 N HCl in dioxane was added (1 mL), and thereaction mixture was heated to 80 degrees for 30 mins. The mixture wasthen diluted with methanol and purified directly on prep-LCMS (XBridgeC18 column, eluting with a gradient of acetonitrile/water containing0.1% TFA, at flow rate of 60 mL/min) to provide the desired product.LC-MS calculated for C₁₇H₁₆F₂N₇ [M+H]⁺ m/z: 356.2, found 356.2.

Example 85.1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylethanamine

Step 1.1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)ethanone

To a solution of3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzaldehyde(100 mg, 0.213 mmol) in THF (2.1 mL) at 0° C. was added methylmagnesiumbromide (1 M in THF, 213 μl, 0.638 mmol). The reaction mixture waswarmed up to r.t. and stirred for 1 hr, and then quenched with sat.ammonium chloride and extracted with ethyl acetate. The organic layerwas dried over sodium sulfate and concentrated. To the residue was addedDCM (2 mL) and manganese dioxide (185 mg, 2.125 mmol). After stirring at60° C. for 1 hr, the mixture was filtered through a plug of Celite andconcentrated. The residue was purified by Biotage Isolera™ (flashpurification system with dichloromethane/methanol at a ratio from 2 to10%) to provide the desired product as a white solid. LCMS calculatedfor C₂₃H₂₇F₂N6O₂Si [M+H]⁺ m/z: 485.2; Found: 485.2.

Step 2.1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylethanamine

A solution of1-(3,5-difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)ethan-1-one(25 mg, 0.052 mmol), methanamine (0.129 ml, 0.258 mmol) in toluene (1ml) was stirred at 80° C. overnight. The reaction mixture was thenconcentrated and redissolved in methanol (1 ml). Sodium borohydride(5.86 mg, 0.155 mmol) was then added, and the mixture was stirred atr.t. for 30 mins. 4N HCl in dioxane was then added and stirring wascontinued at 80° C. for 30 mins. The mixture was then diluted withmethanol and purified directly on prep-LCMS (XBridge C18 column, elutingwith a gradient of acetonitrile/water containing 0.1% TFA, at flow rateof 60 mL/min) to provide the desired product. LC-MS calculated forC₁₈H₁₈F₂N₇ [M+H]⁺ m/z: 370.2, found 370.2.

Example 86.1-(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine

Step 1.(3-Fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

To a solution of (3-fluoro-5-methoxyphenyl)methanol (575 mg, 3.68 mmol)in THF (18 mL) at −78° C. was added n-BuLi (1.6 M in hexanes, 4.8 mL,7.73 mmol) and the reaction mixture was stirred at −78° C. for 1 hr.Then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1581 μl, 7.73mmol) was added dropwise and stirring was continued at −78° C. for 0.5hrs, then the mixture was warmed to r.t. by removal from the cold bath.When room temperature was reached, the reaction mixture was thenquenched with 1N HCl until acidic and extracted with ethyl acetate. Theorganic layer was dried over sodium sulfate and concentrated. The cruderesidue was used in the next step without further purification.

Step 2.(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)methanol

To a mixture of5-chloro-3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoy)methyl)-1H-pyrazolo[4,3-d]pyrimidine(500 mg, 1.370 mmol),(3-fluoro-5-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol(1160 mg, 4.11 mmol), XPhos Pd G2 (108 mg, 0.137 mmol) and potassiumphosphate (582 mg, 2.74 mmol) were added 1,4-dioxane (3.6 mL) and water(900 μl). The reaction flask was evacuated, back filled with nitrogen,and the reaction mixture was then stirred at 95° C. for 2 hours. Themixture was diluted with DCM and filtered through a pad of Celite. Thefiltrate was concentrated and purified by Biotage Isolera™ (flashpurification system with dichloromethane/methanol at a ratio from 2 to10%) to provide the desired product as an oil. LCMS calculated forC₂₃H₃₀FN₆O₃Si [M+H]⁺ m/z: 485.2; Found: 485.2.

Step 3.3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzaldehyde

To a solution of(3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)methanol(309 mg, 0.638 mmol) in DCM (6.4 mL) was added manganese dioxide (554mg, 6.38 mmol) and the reaction mixture was heated to 60° C. for 1 h,then cooled, filtered through a plug of Celite and concentrated. Theresidue was purified by Biotage Isolera™ (flash purification system withdichloromethane/methanol at a ratio from 2 to 10%) to provide thedesired product as an oil. LCMS calculated for C₂₃H₂₈FN₆O₃Si [M+H]⁺ m/z:483.2; Found: 483.2.

Step 4.1-(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine

To a solution of3-fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzaldehyde(25 mg, 0.052 mmol) and methanamine (2 M in THF, 0.130 ml, 0.259 mmol)in toluene (1 ml) was added acetic acid (8.90 μl, 0.155 mmol) and thereaction mixture was heated to 80° C. overnight. The mixture was thencooled down to r.t. and concentrated. The residue was redissolved inMeOH (1 ml) and sodium borohydride (1.960 mg, 0.052 mmol) was added.After 30 mins, 4 N HCl in dioxane was added (1 mL) and the mixtureheated to 80° C. for 30 mins, then diluted with methanol and purifieddirectly on prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toprovide the desired product. LC-MS calculated for C₁₈H₁₉FN₇O [M+H]⁺ m/z:368.2, found 368.2.

Example 87.N-(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-S-yl)benzyl)ethanamine

This compound was prepared using procedures analogous to those forexample 86, with ethyl amine (88% in water) replacing methylamine. LCMScalculated for C₁₉H₂₁FN₇O [M+H]⁺ m/z: 382.2; Found: 382.2.

Example 88.5-(2-Fluoro-6-methoxyphenyl)-3-(3-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared using procedures analogous to those forExample 12, with3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolereplacing phenylboronic acid as starting material. LCMS calculated forC₁₆H₁₄FN₆O [M+H]⁺ m/z: 325.2; Found: 325.2.

Example 89.3-(Benzyloxy)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3d]pyrimidine

To a mixture of5-(2-fluoro-6-methoxyphenyl)-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine(30 mg, 0.060 mmol, Example 12, Step 5), benzyl alcohol (62.3 μL, 0.600mmol), cesium carbonate (58.6 mg, 0.180 mmol) and t-BuBrettPhos Pd G3 (4mg) was added 1,4-dioxane (700 μL). The reaction flask was evacuated,back filled with nitrogen, and the reaction mixture was then stirred at100° C. overnight. The reaction mixture was quenched with water andextracted with ethyl acetate.

The organic layer was dried over sodium sulfate and concentrated. To theresidue were added methanol (1 mL) and HCl (4M in dioxane, 1 mL). Afterstirring at 80° C. for 1 hr, the mixture was diluted with methanol andpurified directly on prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to provide the desired product. LC-MS calculated for C₁₉H₁₆FN₄O₂[M+H]⁺ m/z: 351.2, found 351.2.

Example 90.6,8-Difluoro-7-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

Step 1. N-(3,5-Difluorophenethyl)-2,2,2-trifluoroacetamide

To a solution of 2-(3,5-difluorophenyl)ethan-1-amine (AURUM Pharmatech,5.023 g, 32.0 mmol) in CH₂Cl₂ (100.0 mL) was added triethylamine (9.90mL, 71.0 mmol). The mixture was cooled to −15° C. Then trifluoroaceticanhydride (6.15 mL, 43.6 mmol) was added dropwise. The mixture wasallowed to warm to room temperature. After stirring at room temperaturefor 30 mins, the reaction mixture was poured into ice and extracted withCH₂Cl₂. The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product as a pale yellow solid that wasused directly in the next step without further purification (8.96 g).LCMS calculated for C₁₀H₉F₅NO (M+H)⁺ m/z=254.1; found 254.2.

Step 2.1-(6,8-Difluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethanone

To a solution of N-(3,5-difluorophenethyl)-2,2,2-trifluoroacetamide(6.29 g, 24.84 mmol) in acetic acid (80.0 ml) at 0° C. was addedsulfuric acid (50.0 ml) slowly. Then paraformaldehyde (1.967 g, 65.5mmol) was added. The mixture was allowed to warm to room temperature andstirred for 5 h. The mixture was poured into ice, and extracted withEtOAc. The organic layer was washed with 2 M K2CO₃(aq), dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel (120 g, 0-100% EtOAc in hexanes) to give the desired productas a white solid (3.867 g, 59%). LCMS calculated for C₁₁H₉F₅NO (M+H)⁺m/z=266.1; found 266.1.

Step 3. tert-Butyl6,8-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of1-(6,8-difluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,2,2-trifluoroethan-1-one(3.867 g, 14.58 mmol) in MeOH (70.0 ml) was added potassium carbonate(6.56 g, 47.5 mmol) followed by H2O (25.0 ml). The mixture was stirredat 50° C. for 2 h. After cooling to room temperature, the mixture wasdiluted with CH₂Cl₂ and washed with brine. The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated. The residue wasdissolved in CH₂Cl₂ (50 ml). Boc-anhydride (3.56 g, 16.31 mmol) wasadded followed by DMAP (548.6 mg, 4.49 mmol). The reaction mixture wasstirred at room temperature for 30 mins and MeOH (50 ml) was added. Thereaction was concentrated. The residue was purified on silica gel (120g, 0-50% EtOAc in hexanes) to give the desired product as a colorlessoil (3.77 g, 96%). LCMS calculated for C₁₀H₁₀F₂NO₂ (M+H—C₄H₈)⁺:m/z=214.1; found: 214.1.

Step 4. tert-Butyl6,8-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of tert-butyl6,8-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate (3.76 g, 13.96mmol) in THF (100.0 ml) under N₂ at −78° C. was added a solution of LDA(1.0 M in THF/hexanes) (36.0 ml, 36.0 mmol) dropwise via syringe over aperiod of 40 mins. The reaction was allowed to warm to −60° C. andstirred for 60 mins. The reaction was then cooled back to −78° C.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.52 ml, 51.5mmol) was added slowly over a period of 20 min. After stirring at −78°C. for 20 min, the reaction mixture was allowed to warm to roomtemperature and stirred for 2 h. The reaction mixture was quenched withsat. NaHCO₃, and extracted with Et₂O. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel (120 g, 0-50% EtOAc in hexanes) to give the desired productas a white solid (4.11 g, 75%). LCMS calculated for C₁₆H₂₁BF₂NO₄(M+H—C₄H₈)⁺: m/z=340.2; found: 340.1.

Step 5. tert-Butyl 5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate

To a solution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (3.034 g, 19.63mmol) in CH₂Cl₂ (100.0 ml) was added boc-anhydride (7.15 ml, 30.8 mmol)followed by DMAP (728.8 mg, 5.97 mmol). The reaction was stirred at roomtemperature for 16 h. MeOH (50 ml) was added. The mixture was stirred atroom temperature for 2 h, and then concentrated. The residue waspurified on silica gel (120 g, 0-100% EtOAc in hexanes) to give thedesired product as a white solid (3.78 g, 76%). LCMS calculated forC₁₀H₁₂ClN₄O₂ (M+H)⁺ m/z=255.1; found 255.1.

Step 6. tert-Butyl7-(1-(tert-butoxycarbonyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6,8-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl 5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (1388 mg,5.45 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 807.5 mg, 1.026 mmol) and cesium carbonate (4851 mg, 14.89mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl6,8-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(2.054 g, 5.20 mmol) in 1,4-dioxane (15.00 ml) was added via syringe,followed by water (6.00 ml). The reaction was stirred at 60° C. for 2 h.The separated organic layer was concentrated. The residue was purifiedon silica gel (120 g, 0-100% EtOAc in hexanes) to give the desiredproduct as a yellow foamy solid (2.410 g, 95%). LCMS calculated forC₂₄H27F2N₅NaO₄ (M+Na)⁺ m/z=510.2; found 510.2.

Step 7. tert-Butyl6,8-difluoro-7-(1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a mixture of tert-butyl7-(1-(tert-butoxycarbonyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6,8-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(2410 mg, 4.94 mmol), potassium carbonate (4755 mg, 34.4 mmol) was added1,4-dioxane (25.0 ml) followed by water (25.0 ml). The mixture wasstirred at 80° C. for 10 h. After cooling to room temperature, themixture was diluted with CH₂Cl₂, and washed with brine. The organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated to givethe crude product as a yellow solid that was used directly in the nextstep without further purification. LCMS calculated for C₁₉H₂₀F₂N₅O₂(M+H)⁺ m/z=388.2; found 388.1.

Step 8. tert-Butyl7-(1-(tert-butoxycarbonyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6,8-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of tot-butyl6,8-difluoro-7-(1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(step 7) in DMF (30.0 ml) was added N-iodosuccinimide (1342 mg, 5.96mmol). The mixture was stirred at 80° C. for 90 mins, and then cooled toroom temperature. Boc-anhydride (1753 mg, 8.03 mmol) was added followedby DMAP (243.4 mg, 1.992 mmol). The reaction was stirred at roomtemperature for 20 mins. The mixture was diluted with CH₂Cl₂, and washedwith sat. NaHCO₃ (aq). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified on silicagel (120 g, 0-100% EtOAc in hexanes) to give the desired product as awhite foamy solid (2041 mg, 67% over 2 steps). LCMS calculated forC₂₄H₂₇F2IN₅O₄ (M+H)⁺ m/z=614.1; found 614.1.

Step 9.6,8-Difluoro-7-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

To a screw-cap vial equipped with a magnetic stir bar was added1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(22.5 mg, 0.074 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 6.0 mg, 7.63 μmol) and cesium carbonate (56.7 mg, 0.174mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl7-(1-(tert-butoxycarbonyl)-3-iodo-1H-pyrazolo[4,3d]pyrimidin-5-yl)-6,8-difluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(30.0 mg, 0.049 mmol) in 1,4-dioxane (2.00 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 mins, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₄H₂₅F₂N₈ (M+H)⁺:m/z=463.2; found: 463.3.

Example 91.2-(5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyrimidin-2-ylamino)ethanol

This compound was prepared according to the procedure described inExample 90 (step 9), using2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-ylamino)ethanolinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₀H₁₉F₂N₈O (M+H)⁺:m/z=425.2; found: 425.2.

Example 92.6,8-Difluoro-7-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

This compound was prepared according to the procedure described inExample 90 (step 9), using2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidineinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₃H₂₄F2N9 (M+H)⁺:m/z=464.2; found: 464.3.

Example 93.5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N,N-dimethylpyrimidin-2-amine

This compound was prepared according to the procedure described inExample 90 (step 9), usingN,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amineinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₀H₉F₂N₈ (M+H)⁺:m/z=409.2; found: 409.3.

Example 94.5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N-methylpyrimidin-2-amine

This compound was prepared according to the procedure described inExample 90 (step 9), usingN-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amineinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₁₉H₁₇F₂N₈ (M+H)⁺:m/z=395.2; found: 395.2.

Example 95.N-(4-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)benzyl)methanesulfonamide

This compound was prepared according to the procedure described inExample 90 (step 9), using 4-(methylsulfonamidoethyl)phenylboronic acidinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₂H₂₁F2N6O₂S (M+H)⁺:m/z=471.1; found: 471.2.

Example 96.7-(3-(4-(Azetidin-1-ylsulfonyl)phenyl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)-6,8-difluoro-1,2,3,4-tetrahydroisoquinoline

This compound was prepared according to the procedure described inExample 90 (step 9), using 4-(azetidin-1-ylsulfonyl)phenylboronic acidinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₃H₂₁F₂N6O₂S (M+H)⁺:m/z=483.1; found: 483.2.

Example 97.7-(3-(6-(Difluoromethoxy)pyridin-3-yl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)-6,8-difluoro-1,2,3,4-tetrahydroisoquinoline

This compound was prepared according to the procedure described inExample 90 (step 9), using2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₀H₁₅F₄N₆O (M+H)⁺:m/z=431.1; found: 431.2.

Example 98.4-(5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)morpholine

This compound was prepared according to the procedure described inExample 90 (step 9), using4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholineinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₃H₂₂F₂N₇O (M+H)⁺:m/z=450.2; found: 450.2. ¹H NMR (TFA salt, 500 MHz, DMSO) δ 9.50 (s,1H), 9.30 (br, 2H), 9.17 (d, J=2.2 Hz, 1H), 8.44 (dd, J=9.0, 2.2 Hz,1H), 7.25 (d, J=9.9 Hz, 1H), 7.04 (d, J=9.0 Hz, 1H), 4.35 (s, 2H),3.76-3.66 (m, 4H), 3.57-3.49 (m, 4H), 3.44 (m, 2H), 3.11 (t, J=6.1 Hz,2H).

Example 99.6,8-Difluoro-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

This compound was prepared according to the procedure described inExample 90 (step 9), using1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazineinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₅H₂₆F₂N₇ (M+H)⁺:m/z=462.2; found: 462.3. ¹H NMR (TFA salt, 600 MHz, DMSO) δ 10.12 (br,1H), 9.48 (s, 1H), 9.42 (br, 2H), 8.30 (d, J=8.9 Hz, 2H), 7.25 (d, J=9.8Hz, 1H), 7.16 (d, J=8.9 Hz, 2H), 4.34 (s, 2H), 3.95 (m, 2H), 3.53 (m,2H), 3.45 (m, 2H), 3.17 (m, 2H), 3.11 (t, J=6.1 Hz, 2H), 3.06 (m, 2H),2.86 (s, 3H).

Example 100.8-Methoxy-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

Step 1. tert-Butyl5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate

To a solution of 5-chloro-1H-pyrazolo[4,3-d]pyrimidine (4.97 g, 32.2mmol) in DMF (120.0 ml) was added A-iodosuccinimide (7.967 g, 35.4mmol). The mixture was stirred at 80° C. for 1 h. After cooling to roomtemperature, boc-anhydride (11.32 ml, 48.8 mmol) was added followed byDMAP (1.296 g, 10.61 mmol). The reaction was stirred at room temperaturefor 20 mins. The mixture was diluted with Et₂O and washed with water.The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel (120 g, 0-100%EtOAc in hexanes) to give the desired product as a white solid (4.435 g,49%). LCMS calculated for C₁₀H₁₁ClIN₄O₂ (M+H)⁺ m/z=381.0; found 381.0.

Step 2. tert-Butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl 5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(700.0 mg, 1.839 mmol), (4-(4-methylpiperazin-1-yl)phenyl)boronic acid(509.0 mg, 2.313 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (300.1 mg, 0.367 mmol) and cesium carbonate(1991 mg, 6.11 mmol). The vial was sealed with a Teflon-lined septum,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). 1,4-Dioxane (10.0 ml) was added, followed bywater (3.0 ml). The reaction mixture was stirred at 50° C. for 16 h.After cooling to room temperature, the mixture was diluted with CH₂Cl₂,and washed with brine. The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified on silicagel (40 g, 0-100% EtOAc in hexanes then 10% MeOH in CH₂Cl₂) to give thedesired product as a brown solid (752.2 mg, 95%). LCMS calculated forC₂₁H₂₆ClN₆O₂ (M+H)⁺ m/z=429.2; found 429.2.

Step 3. tert-Butyl5-bromo-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of 5-bromo-8-methoxy-1,2,3,4-tetrahydroisoquinoline, HClsalt (857.7 mg, 3.08 mmol) in CH₂Cl₂ (10.0 ml) was addedMA-diisopropylethylamine (1.209 ml, 6.92 mmol). The mixture was stirredat room temperature for 10 mins, and then a solution of boc-anhydride(828.2 mg, 3.79 mmol) in CH₂Cl₂ (5.0 ml) was added. After stirring atroom temperature for 30 mins, the reaction was concentrated. The residuewas purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give thedesired product as an oil (1.048 g, 99%). LCMS calculated forC₁₁H₁₃BrNO₃ (M+H—C₄H₈)⁺: m/z=286.0; found: 286.0.

Step 4. tert-Butyl8-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a screw-cap vial equipped with a magnetic stir bar was added4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (1174 mg,4.62 mmol), potassium acetate (1214 mg, 12.37 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (500.3 mg, 0.613 mmol). The vial was sealedwith a Teflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of tert-butyl5-bromo-8-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (1048 mg,3.06 mmol) in 1,4-dioxane (15.0 mL) was added via syringe. The mixturewas stirred at 100° C. for 16 h. After cooling to room temperature, thereaction mixture was diluted with CH₂Cl₂ and filtered. The filtrate wasconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product (959.8 mg, 81%). LCMS calculatedfor C₁₇H₂₅BNO₅ (M+H—C₄H₈)⁺: m/z=334.2; found: 334.1.

Step 5.8-Methoxy-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(39.7 mg, 0.093 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 9.0 mg, 0.011 mmol) and cesium carbonate (81.5 mg, 0.250mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl8-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(29.7 mg, 0.076 mmol) in 1,4-dioxane (2.00 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 min, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₆H₃₀N₇O (M+H)⁺:m/z=456.3; found: 456.2.

Example 101.8-Fluoro-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)quinoline

This compound was prepared according to the procedure described inExample 100 (step 5), using 8-fluoroquinolin-7-ylboronic acid instead oftert-butyl8-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylateas the starting material. LCMS calculated for C₂₅H₂₃FN₇ (M+H)⁺:m/z=440.2; found: 440.2.

Example 102.5-(4-Methoxypyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine

This compound was prepared according to the procedure described inExample 100 (step 5), using 4-methoxypyridin-3-ylboronic acid instead oftert-butyl8-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylateas the starting material. LCMS calculated for C₂₂H₂₄N₇O (M+H)⁺:m/z=402.2; found: 402.2.

Example 103.5-(4-Methoxypyridin-3-yl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine

Step 1. tert-Butyl5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl 5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(900.0 mg, 2.365 mmol),1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(732.2 mg, 2.415 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexedwith dichloromethane (1:1) (386.1 mg, 0.473 mmol) and cesium carbonate(2621 mg, 8.04 mmol). The vial was sealed with a Teflon-lined septum,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). 1,4-Dioxane (10.0 ml) was added, followed bywater (3.0 ml). The reaction was stirred at 50° C. for 16 h. Aftercooling to room temperature, the mixture was diluted with CH₂Cl₂, andwashed with brine. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified on silica gel (40 g,0-100% EtOAc in hexanes then 10% MeOH in CH₂Cl₂) to give the desiredproduct as a yellow solid (746.2 mg, 73%). LCMS calculated forC₂OH₂₅ClN₇O₂ (M+H)⁺ m/z=430.2; found 430.2.

Step 2.5-(4-Methoxypyridin-3-yl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(24.7 mg, 0.057 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 7.0 mg, 8.90 μmol) and cesium carbonate (66.2 mg, 0.203mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of (4-methoxypyridin-3-yl)boronic acid (23.6 mg,0.154 mmol) in 1,4-dioxane (2.00 ml) was added via syringe, followed bywater (200.0 μl). The reaction was heated to 50° C. for 16 h. Thereaction was concentrated. To the residue was added CH₂Cl₂ (2.0 mL)followed by TFA (2.0 mL). The mixture was stirred at room temperaturefor 15 min, and then concentrated. The residue was purified usingprep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₁H₂₃N₈O (M+H)⁺:m/z=403.2; found: 403.2.

Example 104.N-Methyl-1-(4-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)pyridin-2-yl)methanamine

Step 1. tert-Butyl (5-bromo-4-methylpyridin-2-yl)methyl(methyl)carbamate

To a solution of 5-bromo-4-methylpicolinaldehyde (1.044 g, 5.22 mmol) inMeOH (20.0 ml) was added 2.0 M methylamine in MeOH (8.0 ml, 16.00 mmol)followed by sodium cyanoborohydride (1.313 g, 20.89 mmol) and aceticacid (1.00 ml, 17.47 mmol). After stirring at room temperature for 90mins, the reaction was quenched with HCl (6.0 N in water) (25.0 ml, 150mmol). The mixture was stirred at room temperature for 30 mins, andtreated with NaOH (4 N in water) until pH reached 10. The mixture wasextracted with Et₂O. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was dissolved in CH₂Cl₂ (30 mL),and treated with Boc-anhydride (1.198 g, 5.49 mmol). After stirring atroom temperature for 30 mins, the reaction was concentrated. The residuewas purified on silica gel (40 g, 0-100% EtOAc in hexanes) to give thedesired product as a yellow oil (1.101 g, 67%). LCMS calculated forC₁₃H₂₀BrN₂O₂ (M+H)⁺ m/z=315.1; found 315.0.

Step 2. tert-Butylmethyl((4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate

To a screw-cap vial equipped with a magnetic stir bar was added4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (1.216 g,4.79 mmol), potassium acetate (1.143 g, 11.65 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (450.3 mg, 0.551 mmol). The vial was sealedwith a Teflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of tert-butyl((5-bromo-4-methylpyridin-2-yl)methyl)(methyl)carbamate (1.101 g, 3.49mmol) in 1,4-dioxane (17.0 ml) was added via syringe. The mixture wasstirred at 80° C. for 16 h. After cooling to room temperature, thereaction mixture was diluted with CH₂Cl₂ and filtered. The filtrate wasconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes then 10% MeOH in CH₂Cl₂) to give the desired product (461.0mg, 36%).

Step 3.N-Methyl-1-(4-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)pyridin-2-yl)methanamine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(47.0 mg, 0.110 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 13.0 mg, 0.017 mmol) and cesium carbonate (115.5 mg, 0.354mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butylmethyl((4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate(59.8 mg, 0.165 mmol) in 1,4-dioxane (3.00 ml) was added via syringe,followed by water (300.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 mins, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₄H₂₉N₈ (M+H)⁺:m/z=429.3; found: 429.3.

Example 105.2-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)acetonitrile

Step 1. 4-(4-Bromo-3,5-difluorophenyl)isoxazole

To a screw-cap vial equipped with a magnetic stir bar was added2-bromo-1,3-difluoro-5-iodobenzene (1360.8 mg, 4.27 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (828.0 mg, 4.25mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (727.0 mg, 0.890 mmol) and cesium carbonate (2843mg, 8.73 mmol). The vial was sealed with a Teflon-lined septum,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). 1,4-Dioxane (12.0 ml) was added via syringefollowed by water (2.0 ml). The reaction was heated to 50° C. for 16 h.After cooling to room temperature, the organic layer was separated andconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product as a pale yellow solid (502.9mg, 46%).

Step 2. 2-(4-Bromo-3,5-difluorophenyl)acetonitrile

To a mixture of 4-(4-bromo-3,5-difluorophenyl)isoxazole (489.4 mg, 1.882mmol) and potassium fluoride (584.8 mg, 10.07 mmol) was added DMF (5.0ml) followed by water (5.0 ml). The reaction was heated to 90° C. for 3h. After cooling to room temperature, the mixture was diluted withCH₂Cl₂, and washed with brine. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel (40 g, 0-100% EtOAc in hexanes) to give the desired productas an off-white solid (363.4 mg, 83%).

Step 3.2-(3,5-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile

To a screw-cap vial equipped with a magnetic stir bar was added4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (607.8mg, 2.393 mmol), potassium acetate (643.7 mg, 6.56 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexedwith dichloromethane (1:1) (256.1 mg, 0.314 mmol). The vial was sealedwith a Teflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of2-(4-bromo-3,5-difluorophenyl)acetonitrile (363.4 mg, 1.566 mmol) in1,4-dioxane (10.0 mL) was added via syringe. The mixture was stirred at100° C. for 16 h. After cooling to room temperature, the reactionmixture was diluted with CH₂Cl₂ and filtered. The filtrate wasconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes then 10% MeOH in CH₂Cl₂) to give the desired product (229.4mg, 53%). LCMS calculated for C₁₄H₁₇BF₂NO₂ (M+H)⁺: m/z=280.1; found:280.0.

Step 4. tert-Butyl5-chloro-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl 5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(1026.0 mg, 2.70 mmol),2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(816.5 mg, 2.68 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (440.2 mg, 0.539 mmol) and cesium carbonate(2693 mg, 8.27 mmol). The vial was sealed with a Teflon-lined septum,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). 1,4-Dioxane (12.0 ml) was added, followed bywater (4.0 ml). The reaction was stirred at 50° C. for 16 h. Aftercooling to room temperature, the mixture was diluted with CH₂Cl₂, andwashed with brine. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified on silica gel (40 g,0-100% EtOAc in hexanes then 10% MeOH in CH₂Cl₂) to give the desiredproduct as a yellow solid (877.3 mg, 76%). LCMS calculated forC₁₉H₂₄ClN₈O₂ (M+H)⁺ m/z=431.2; found 431.1.

Step 5.2-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)acetonitrile

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(33.3 mg, 0.077 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(9.0 mg, 0.011 mmol) and cesium carbonate (83.0 mg, 0.255 mmol). Thevial was sealed with a Teflon-lined septum, evacuated and backfilledwith nitrogen (this process was repeated a total of three times). Asolution of2-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile(34.6 mg, 0.124 mmol) in 1,4-dioxane (2.0 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 mins, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₂H₂₀F₂N₉ (M+H)⁺:m/z=448.2; found: 448.2.

Example 106.6-Fluoro-5-(3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

Step 1. 5-Bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline

To a solution of 5-bromo-6-fluoroisoquinoline (1.002 g, 4.433 mmol) inacetic acid (20.0 mL) at room temperature was added sodiumtetrahydroborate (592.0 mg, 15.65 mmol) portion wise. The mixture wasstirred at room temperature for 16 h, and then concentrated. The residuewas diluted with CH₂Cl₂ and washed with 2 M Na₂CO₃ (aq). The separatedorganic layer was dried over anhydrous Na₂SO₄, filtered and concentratedto give a yellow oil that was used directly in the next step withoutfurther purification. LCMS calculated for C₉H₁₀BrFN (M+H)⁺ m/z=230.0;found 230.1.

Step 2. tert-Butyl5-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of 5-bromo-6-fluoro-1,2,3,4-tetrahydroisoquinoline (1.020g, 4.433 mmol) in CH₂Cl₂ (12.0 mL) was added di-tert-butyl dicarbonate(1.617 g, 7.409 mmol). The mixture was stirred at room temperature for 1h, and then concentrated. The residue was purified on silica gel (120 g,0-100% EtOAc in hexanes) to give the desired product as a white solid(1.119 g, 76% over two steps). LCMS calculated for C₁₄H₁₇BrFNNaO₂(M+Na)⁺ m/z=352.0; found 352.0.

Step 3. tert-Butyl6-fluoro-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl 5-bromo-6-fluoro-3,4-dihydroisoquinoline-2(1H)-carboxylate(1.119 g, 3.389 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (1.358 g,5.348 mmol), potassium acetate (1.101 g, 11.22 mmol), and[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (298.6 mg, 0.366 mmol). The vial was sealedwith a Teflon-lined septum, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). 1,4-Dioxane (15.0 mL) wasadded via syringe. The mixture was heated at 100° C. for 16 h. Aftercooling to room temperature, the reaction mixture was diluted withCH₂Cl₂ and filtered. The filtrate was concentrated. The residue waspurified on silica gel (40 g, 0-100% EtOAc in hexanes) to give thedesired product as a pale yellow oil (1001 mg, 78%). LCMS calculated forC₂₀H₂₉BFNNaO₄ (M+Na)⁺ m/z=400.2; found 400.2.

Step 4. tert-Butyl5-chloro-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl 5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(1126.0 mg, 2.96 mmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine(949.2 mg, 3.00 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (450.5 mg, 0.552 mmol) and cesium carbonate(2892.3 mg, 8.88 mmol). The vial was sealed with a Teflon-lined septum,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). 1,4-Dioxane (12.0 ml) was added via syringe,followed by water (4.0 ml). The reaction was stirred at 50° C. for 16 h.After cooling to room temperature, the mixture was diluted with CH₂Cl₂,and washed with brine. The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified on silicagel (40 g, 0-100% EtOAc in hexanes then 10% MeOH in CH₂Cl₂) to give thedesired product as a yellow solid (927.3 mg, 71%). LCMS calculated forC₂₂H₂₈ClN₆O₂ (M+H)⁺ m/z=443.2; found 443.2.

Step 5.6-Fluoro-5-(3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(26.5 mg, 0.060 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 7.0 mg, 8.90 μmol) and cesium carbonate (68.0 mg, 0.209mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(22.6 mg, 0.060 mmol) in 1,4-dioxane (2.0 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction mixture was concentrated. To the residue was addedCH₂Cl₂ (2.0 mL) followed by TFA (2.0 mL). The resulting mixture wasstirred at room temperature for 15 min, and then concentrated. Theresidue was purified using prep-LCMS (XBridge C18 column, eluting with agradient of acetonitrile/water containing 0.1% TFA, at flow rate of 60mL/min) to afford the desired product. LCMS calculated for C₂₆H₂₉FN₇(M+H)⁺: m/z=458.2; found: 458.3.

Example 107.6-Fluoro-8-methyl-7-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

Step 1. (3-Bromo-4-fluoro-2-methylphenyl)methanol

To a solution of ethyl 3-bromo-4-fluoro-2-methylbenzoate (Enamine, 6.535g, 25.03 mmol) in THF (60.0 ml) was added BH₃*THF (1.0 M in THF) (125ml, 125 mmol). The mixture was stirred at 65° C. for 16 h. The reactionwas cooled to room temperature, and MeOH (100.0 ml) was added. Afterstirring at room temperature for 2 h, the mixture was cooled to 0° C.HCl (4.0 M in water) (100 ml, 400 mmol) was added. The mixture wasextracted with Et₂O. The separated organic layer was washed with sat.NaHCO₃, dried over anhydrous Na₂SO₄, filtered and concentrated to givethe crude product as a white solid (5.35 g, 98%).

Step 2. 3-Bromo-4-fluoro-2-methylbenzaldehyde

To a solution of (3-bromo-4-fluoro-2-methylphenyl)methanol (5.35 g,24.42 mmol) in CH₂Cl₂ (120.0 ml) was added manganese dioxide (activated)(36.6 g, 379 mmol). The mixture was stirred at room temperature for 16h. The mixture was filtered through a pad of Celite. The Celite pad wasfurther rinsed with CH₂Cl₂. The combined filtrate was concentrated. Theresidue was purified on silica gel (120 g, 0-100% EtOAc in hexanes) togive the desired product as a yellow solid (4.427 g, 84%).

Step 3. N-(3-Bromo-4-fluoro-2-methylbenzylidene)-2,2-dimethoxyethanamine

To a solution of 3-bromo-4-fluoro-2-methylbenzaldehyde (6.086 g, 28.0mmol) in toluene (100.0 ml) was added 2,2-dimethoxyethan-1-amine (3.13mL, 28.6 mmol). The mixture was refluxed for 16 h with a Dean-Starktrap. After cooling to room temperature, the mixture was concentrated togive the crude product that was used directly in next step withoutfurther purification. LCMS calculated for C₁₂H₁₆BrFNO₂ (M+H)⁺ m/z=304.0;found 304.0.

Step 4. 7-Bromo-6-fluoro-8-methylisoquinoline

To a solution of1-(3-bromo-4-fluoro-2-methylphenyl)-N-(2,2-dimethoxyethyl)methanimine(crude in step 3) in THF (100.0 ml) at −10° C. was added ethylchloroformate (3.126 g, 28.8 mmol) dropwise. The mixture was stirred at−10° C. for 10 mins, and then allowed to warm to room temperature andstirred for 2 h. Trimethyl phosphite (4.562 g, 36.8 mmol) was added. Themixture was stirred at room temperature for 24 h, and then concentrated.The resulting oil was re-evaporated three times with toluene to removetraces of trimethyl phosphite. The residue was dissolved in CH₂Cl₂(100.0 ml). A solution of TiCl₄ (1.0 M in CH₂Cl₂) (200.0 ml, 200 mmol)was added. The mixture was refluxed under N₂ for 72 h. After cooling toroom temperature, the mixture was poured into ice and treated withammonium hydroxide (14.8 M in water) until pH reached 10. The mixturewas filtered through a pad of Celite. The pad was rinsed with CH₂Cl₂.The organic layer was separated, dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified on silica gel (120 g, 0-100%EtOAc in hexanes) to give the desired product as a white solid (3.378 g,50% over 2 steps). LCMS calculated for C₁₀H₈BrFN (M+H)⁺ m/z=240.0; found240.0.

Step 5. tert-Butyl7-bromo-6-fluoro-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of 7-bromo-6-fluoro-8-methylisoquinoline (3.378 g, 14.07mmol) in acetic acid (100.0 ml) at room temperature was added sodiumtetrahydroborate (2042.3 mg, 54.0 mmol) portion wise. The mixture wasstirred at room temperature for 1 h, and MeOH (100 ml) was added. Themixture was concentrated. The residue was diluted with CH₂Cl₂, andwashed with 2 M K₂CO₃ (aq). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was dissolved in CH₂Cl₂.Boc-anhydride (4.27 g, 19.56 mmol) was added followed by DMAP (534.8 mg,4.38 mmol). After stirring at room temperature for 40 min, the mixturewas treated with MeOH (20 ml) and stirred for 2 h. The mixture was thenconcentrated. The residue was purified on silica gel (120 g, 0-50% EtOAcin hexanes) to give the desired product as a pale yellow solid (2.13 g,44%). LCMS calculated for C₁₁H₁₂BrFNO₂ (M+H—C₄H₈)⁺: m/z=288.0; found:288.0.

Step 6. tert-Butyl6-fluoro-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl7-bromo-6-fluoro-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(1083.9 mg, 3.15 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (1076 mg,4.24 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)complexed with dichloromethane (1:1) (514 mg, 0.630 mmol) and potassiumacetate (982.3 mg, 10.01 mmol). The vial was sealed with a Teflon-linedseptum, evacuated and backfilled with nitrogen (this process wasrepeated a total of three times). 1,4-Dioxane (12.0 mL) was added viasyringe. The mixture was stirred at 100° C. for 16 h. After cooling toroom temperature, the reaction mixture was filtered. The filtrate wasused directly in the next step.

Step 7. tert-Butyl7-(1-(tert-butoxycarbonyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6-fluoro-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl 5-chloro-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate (882.4mg, 3.46 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 372.5 mg, 0.473 mmol) and cesium carbonate (3138 mg, 9.63mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl6-fluoro-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(step 6) in 1,4-dioxane (12.0 ml) was added via syringe, followed bywater (4.0 ml). The reaction was stirred at 50° C. for 16 h. Aftercooling to room temperature, the mixture was diluted with CH₂Cl₂ andwashed with brine. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified on silica gel (40 g,0-100% EtOAc in hexanes) to give the desired product as a yellow foamysolid (735.5 mg, 48% over two steps). LCMS calculated for C₂₅H₃₁FN₅O₄(M+H)⁺: m/z=484.2; found: 484.2.

Step 8. tert-Butyl6-fluoro-8-methyl-7-(1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of tert-butyl7-(1-(tert-butoxycarbonyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6-fluoro-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(735.5 mg, 1.521 mmol) in 1,4-dioxane (8.0 ml) was added potassiumcarbonate (1552 mg, 11.23 mmol) followed by water (8.0 ml). The mixturewas stirred at 80° C. for 10 h. After cooling to room temperature, themixture was diluted with Et₂O and washed with brine. The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated to give thecrude product as a yellow solid that was used directly in the next stepwithout further purification. C₂₀H₂₃FN₅O₂ (M+H)⁺: m/z=384.2; found:384.1.

Step 9. tert-Butyl7-(1-(tert-butoxycarbonyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6-fluoro-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of tert-butyl6-fluoro-8-methyl-7-(1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(step 8) in DMF (10.0 ml) was added N-iodosuccinimide (412.4 mg, 1.833mmol). The mixture was stirred at 60° C. for 90 mins, and cooled to roomtemperature. Boc-anhydride (494.2 mg, 2.264 mmol) was added followed byDMAP (77.8 mg, 0.637 mmol). The reaction was stirred at room temperaturefor 30 mins. The mixture was diluted with CH₂Cl₂ and washed with sat.NaHCO₃(aq). The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified on silica gel (40 g, 0-100%EtOAc in hexanes) to give the desired product (198.1 mg, 21% over 2steps). LCMS calculated for C₂₅H₃₀FIN₅O₄ (M+H)⁺: m/z=610.1; found:610.1.

Step 10.6-Fluoro-8-methyl-7-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

To a screw-cap vial equipped with a magnetic stir bar was added1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine(18.0 mg, 0.059 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 5.0 mg, 6.35 μmol) and cesium carbonate (50.1 mg, 0.154mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl7-(1-(tert-butoxycarbonyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6-fluoro-8-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate(25.0 mg, 0.041 mmol) in 1,4-dioxane (2.00 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 mins, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₅H₂₈FN₈ (M+H)⁺:m/z=459.2; found: 459.2.

Example 108.1-(4-(4-(5-(6-Fluoro-8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)piperazin-1-yl)ethanone

This compound was prepared according to the procedure described inExample 107 (step 10), using1-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazin-1-yl)ethanoneinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₇H₂₉FN₇O (M+H)⁺:m/z=486.2; found: 486.3.

Example 109.4-(5-(5-(6-Fluoro-8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)morpholine

This compound was prepared according to the procedure described inExample 107 (step 10), using4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholineinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₄H₂₅FN₇O (M+H)⁺:m/z=446.2; found: 446.3.

Example 110.6-Fluoro-8-methyl-7-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

This compound was prepared according to the procedure described inExample 107 (step 10), using1-methyl-4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₅H₂₈FN₈ (M+H)⁺:m/z=459.2; found: 459.2.

Example 111.6-Fluoro-8-methyl-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

This compound was prepared according to the procedure described inExample 107 (step 10), using1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazineinstead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazineas the starting material. LCMS calculated for C₂₆H₂₉FN₇ (M+H)⁺:m/z=458.2; found: 458.3. ¹H NMR (TFA salt, 500 MHz, DMSO) δ 10.14 (br,1H), 9.46 (s, 1H), 9.36 (br, 2H), 8.29 (d, J=8.9 Hz, 2H), 7.14 (m, 3H),4.25 (s, 2H), 3.93 (m, 2H), 3.52 (m, 2H), 3.40 (m, 2H), 3.16 (m, 2H),3.09 (t, J=6.1 Hz, 2H), 3.03 (m, 2H), 2.86 (s, 3H), 1.98 (s, 3H).

Example 112.8-Fluoro-6-methyl-7-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

Step 1. tert-Butyl8-fluoro-6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

This compound was prepared according to the procedures described inExample 107 (step 3 to step 6), using3-bromo-2-fluoro-4-methylbenzaldehyde (AstaTech) instead of3-bromo-4-fluoro-2-methylbenzaldehyde (step 2 in Example 107) as thestarting material. LCMS calculated for C₂₁H₃₁BFNNaO₄ (M+Na)⁺: m/z=414.2;found: 414.2.

Step 2.8-Fluoro-6-methyl-7-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(42.8 mg, 0.100 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 9.0 mg, 0.011 mmol) and cesium carbonate (84.3 mg, 0.259mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl8-fluoro-6-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate(31.7 mg, 0.081 mmol) in 1,4-dioxane (2.00 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 min, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₅H₂₈FN₈ (M+H)⁺:m/z=459.2; found: 459.2. ¹H NMR (TFA salt, 600 MHz, DMSO) δ 10.09 (br,1H), 9.49 (s, 1H), 9.29 (br, 2H), 9.20-9.18 (m, 1H), 8.48 (dd, J=8.8,2.3 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.11 (s, 1H), 4.48 (m, 2H), 4.31(s, 2H), 3.52 (m, 2H), 3.46-3.36 (m, 2H), 3.20 (m, 2H), 3.06 (m, 4H),2.84 (s, 3H), 2.17 (s, 3H).

Example 113.4,6-Difluoro-N-methyl-5-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine

Step 1. tert-Butyl4,6-difluoro-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

To a solution of 4,6-difluoro-2,3-dihydro-1H-inden-1-one (Ark Pharm,4.015 g, 23.88 mmol) in 2-propanol (90.0 ml) was added methylamine (2.0M in methanol) (60.0 ml, 120 mmol) followed by titanium(IV) isopropoxide(15.31 ml, 51.7 mmol). The mixture was stirred at 35° C. for 16 h beforeit was cooled to room temperature. Sodium borohydride (1.312 g, 34.7mmol) was added. The reaction was stirred at room temperature for 1 h,and was quenched with HCl (6.0 N in water) (60.0 ml, 360 mmol). Themixture was stirred at room temperature for 2 h, and was treated withNaOH (4.0 N in water) until pH reached 10. The mixture was extractedwith Et₂O. The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was dissolved in CH₂Cl₂ (100 mL), andtreated with boc-anhydride (5.21 g, 23.88 mmol). After stirring at roomtemperature for 30 min, the reaction was concentrated. The residue waspurified on silica gel (120 g, 0-100% EtOAc in hexanes) to give thedesired product as an oil (5.27 g, 78%). LCMS calculated for C₁₁H₁₂F₂NO₂(M+H—C₄H8)⁺: m/z=228.1; found: 228.1.

Step 2. tert-Butyl4,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl(methyl)carbamate

To a solution of tert-butyl(4,6-difluoro-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (5.27 g, 18.60mmol) in THF (100.0 ml) at −78° C. under N₂ was added a solution ofn-BuLi (2.5 M in hexanes) (15.00 ml, 37.5 mmol) slowly over a period of20 min. The reaction was allowed to warm to −60° C. and stirred for 90min. The reaction was then cooled back to −78° C.2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (10.79 g, 58.0mmol) was added slowly over a period of 20 min. After stirring at −78°C. for another 10 min, the reaction was allowed to warm to roomtemperature and stirred for 1 h. The reaction was then quenched withsat. NaHCO₃, and extracted with Et₂O. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified on silicagel (120 g, 0-100% EtOAc in hexanes) to give the desired product as anoil (1.74 g, 23%). LCMS calculated for C₁₇H₂₃BF₂NO₄ (M+H—C₄H₈)⁺:m/z=354.2; found: 354.1.

Step 3. tert-Butyl5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl 5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(463.9 mg, 1.219 mmol),4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)morpholine(468.2 mg, 1.614 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexedwith dichloromethane (1:1) (149.2 mg, 0.183 mmol) and cesium carbonate(1.2 g, 3.69 mmol). The vial was sealed with a Teflon-lined septum,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). 1,4-Dioxane (10.0 ml) was added, followed bywater (3.0 ml). The reaction was stirred at 50° C. for 4 h. Aftercooling to room temperature, the mixture was diluted with CH₂Cl₂, andwashed with brine. The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was purified on silica gel (40 g,0-100% EtOAc in hexanes) to give the desired product as a yellow solid(395.2 mg, 78%). LCMS calculated for C₁₉H₂₂ClN₆O₃ (M+H)⁺ m/z=417.1;found 417.1.

Step 4.4,6-Difluoro-N-methyl-5-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(24.8 mg, 0.059 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 5.6 mg, 7.12 μmol) and cesium carbonate (58.6 mg, 0.180mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(4,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate(24.8 mg, 0.061 mmol) in 1,4-dioxane (2.00 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 min, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₄H₂₄F₂N₇O (M+H)⁺:m/z=464.2; found: 464.2.

Example 114.4,6-Difluoro-N-methyl-5-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine

Step 1. tert-Butyl5-chloro-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl 5-chloro-3-iodo-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(1026.0 mg, 2.70 mmol),2-(4-methylpiperazin-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(816.5 mg, 2.68 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (330.2 mg, 0.404 mmol) and cesium carbonate(2.693 g, 8.27 mmol). The vial was sealed with a Teflon-lined septum,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). 1,4-Dioxane (12.0 ml) was added, followed bywater (4.0 ml). The reaction was stirred at 50° C. for 16 h. Aftercooling to room temperature, the mixture was diluted with CH₂Cl₂, washedwith brine. The organic layer was dried over anhydrous Na₂SO₄, filteredand concentrated. The residue was purified on silica gel (40 g, 0-100%EtOAc in hexanes, then 10% MeOH in CH₂Cl₂) to give the desired productas a yellow foamy solid (877.3 mg, 76%). LCMS calculated forC₁₉H₂₄ClN₈O₂ (M+H)⁺ m/z=431.2; found 431.1.

Step 2.4,6-Difluoro-N-methyl-5-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(81.4 mg, 0.189 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 28.4 mg, 0.036 mmol) and cesium carbonate (110.9 mg, 0.340mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(4,6-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate(64.0 mg, 0.156 mmol) in 1,4-dioxane (3.00 ml) was added via syringe,followed by water (300.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 mins, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₄H26F2N9 (M+H)⁺:m/z=478.2; found: 478.2.

Example 115.6,8-Difluoro-N-methyl-7-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-2-amine

Step 1. tert-Butyl6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl(methyl)carbamate

To a solution of 6,8-difluoro-3,4-dihydronaphthalen-2(1H)-one (ArkPharm, 1.316 g, 7.22 mmol) in MeOH (30.0 ml) was added methylaminehydrochloride (5.38 g, 80 mmol), sodium cyanoborohydride (2.398 g, 38.2mmol) and THF (30.0 ml). The mixture was heated to 50° C. for 16 h.After cooling to room temperature, the mixture was quenched with HCl(6.0 N in water) (30.0 ml, 180 mmol). The mixture was stirred at roomtemperature for 2 h, and was treated with NaOH (4.0 N in water) until pHreached 10. The mixture was extracted with Et₂O. The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated. The residue wasdissolved in CH₂Cl₂ (100 mL), and treated with Boc-anhydride (1.548 g,7.09 mmol). After stirring at room temperature for 30 min, the reactionwas concentrated. The residue was purified on silica gel (40 g, 0-100%EtOAc in hexanes) to give the desired product as a white solid (1.177 g,55%). LCMS calculated for C₁₂H₁₄F₂NO₂ (M+H—C₄H8)⁺: m/z=242.1; found:242.1.

Step 2. tert-Butyl6,8-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl(methyl)carbamate

To a solution of tert-butyl(6,8-difluoro-1,2,3,4-tetrahydronaphthalen-2-yl)(methyl)carbamate (1.177g, 3.96 mmol) in THF (30.0 ml) at −78° C. under N₂ was added a solutionof n-BuLi (2.5 M in hexanes) (3.20 ml, 8.00 mmol) slowly over a periodof 20 mins. The reaction was allowed to warm to −60° C. and stirred for60 mins. The reaction was then cooled back to −78° C.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.425 ml, 11.89mmol) in THF (10.0 mL) was added slowly over a period of 20 mins. Afterstirring at −78° C. for 20 mins, the reaction was allowed to warm toroom temperature and stirred for 1 h. The reaction was quenched withsat. NaHCO₃, and extracted with Et₂O. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel (40 g, 0-100% EtOAc in hexanes) to give the desired productas a white solid (922.0 mg, 55%). LCMS calculated for C₂₂H₃₂BF₂NNaO₄(M+Na)⁺: m/z=446.2; found: 446.2.

Step 3.6,8-Difluoro-N-methyl-7-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-2-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(24.8 mg, 0.059 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 7.0 mg, 8.90 μmol) and cesium carbonate (58.5 mg, 0.180mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(6,8-difluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl)(methyl)carbamate(22.3 mg, 0.053 mmol) in 1,4-dioxane (2.00 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 mins, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₅H₂₆F₂N₇O (M+H)⁺:m/z=478.2; found: 478.3.

Example 116.5,7-Difluoro-N-methyl-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

Step 1. tert-Butyl5,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate

To a solution of 5,7-difluoro-3,4-dihydronaphthalen-1 (2H)-one (ArkPharm, 1.325 g, 7.27 mmol) in 2-propanol (30.0 ml) was added methylamine(2.0 M in methanol) (15.00 ml, 30.0 mmol) followed by titanium(IV)isopropoxide (4.06 ml, 13.73 mmol) and THF (15.0 ml). The mixture wasstirred at 35° C. for 16 h before it was cooled to room temperature.Sodium borohydride (418.4 mg, 11.06 mmol) was added. The reaction wasstirred at room temperature for 1 h, and was quenched with HCl (6.0 N inwater) (40.0 ml, 240 mmol). The mixture was stirred at room temperaturefor 2 h, and was treated with NaOH (4.0 N in water) until pH reached 10.The mixture was extracted with Et₂O. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was dissolvedin CH₂Cl₂ (40 mL), and treated with Boc-anhydride (1.709 g, 7.83 mmol).After stirring at room temperature for 30 mins, the reaction wasconcentrated. The residue was purified on silica gel (120 g, 0-100%EtOAc in hexanes) to give the desired product (1.873 g, 87%). LCMScalculated for C₁₂H₁₄F₂NO₂ (M+H—C₄H8)⁺: m/z=242.1; found: 242.1.

Step 2. tert-Butyl5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate

To a solution of tert-butyl(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate (1.872g, 6.30 mmol) in THF (40.0 ml) at −78° C. under N₂ was added a solutionof n-BuLi (2.5 M in hexanes) (5.00 ml, 12.50 mmol) slowly over a periodof 20 mins. The reaction was allowed to warm to −60° C. and stirred for60 mins. The reaction was then cooled back to −78° C.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.85 ml, 18.89mmol) in THF (10.0 mL) was added slowly over a period of 20 mins. Afterstirring at −78° C. for 20 mins, the reaction was allowed to warm toroom temperature and stirred for 1 h.

The reaction was quenched with sat. NaHCO₃, and extracted with Et₂O. Theorganic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product as a yellow foamy solid (989.9mg, 37%). LCMS calculated for C₂₂H₃₂BF₂NNaO₄ (M+Na)⁺: m/z=446.2; found:446.2.

Step 3.5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(24.8 mg, 0.059 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 7.0 mg, 8.90 μmol) and cesium carbonate (59.7 mg, 0.183mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate(23.3 mg, 0.055 mmol) in 1,4-dioxane (2.00 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 min, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated C₂₅H₂₆F₂N₇O (M+H)⁺:m/z=478.2; found: 478.2.

Example 117.5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

Step 1. tert-Butyl5,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate

To a mixture of 5,7-difluoro-3,4-dihydronaphthalen-1 (2H)-one (ArkPharm, 1636.4 mg, 8.98 mmol), sodium cyanoborohydride (6.064 g, 96 mmol)and ammonium acetate (16.51 g, 214 mmol) was added 2-propanol (50.0 ml).The reaction was stirred at 70° C. for 16 h. After cooling to roomtemperature, the mixture was diluted with water and extracted with Et₂O.The organic layer was dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was dissolved in THF (100 ml), and HCl (6.0 Nin water) (50.0 ml, 300 mmol) was added. The mixture was stirred at roomtemperature for 16 h, and was treated with NaOH (4.0 N in water) untilpH reached 10. The mixture was extracted with Et₂O. The organic layerwas dried over anhydrous Na₂SO₄, filtered and concentrated. The residuewas dissolved in CH₂Cl₂ (40 ml), and was treated with boc-anhydride(1.982 g, 9.08 mmol). After stirring at room temperature for 30 mins,the reaction was concentrated. The residue was purified on silica gel(120 g, 0-100% EtOAc in hexanes) to give the desired product as a whitesolid (1.836 g, 72%). LCMS calculated for C₁₁H₁₂F₂NO₂ (M+H—C₄H₈)⁺:m/z=228.1; found: 228.1.

Step 2. tert-Butyl5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate

To a solution of tert-butyl(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (1.836 g, 6.48mmol) in THF (40.0 ml) at −78° C. under N₂ was added a solution ofn-BuLi (2.5 M in hexanes) (7.00 ml, 17.50 mmol) slowly via syringe overa period of 20 mins. The reaction was allowed to warm to −60° C. andstirred for 60 mins. The reaction was then cooled back to −78° C.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.04 ml, 24.72mmol) in THF (10.0 ml) was added via syringe slowly over a period of 20mins. After stirring at −78° C. for 20 mins, the reaction was allowed towarm to room temperature and stirred for 1 h. The reaction was quenchedwith sat. NaHCO₃, and extracted with Et₂O. The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified on silica gel (40 g, 0-100% EtOAc in hexanes) to give thedesired product as a white foamy solid (1.632 g, 62%). LCMS calculatedfor C₂₁H₃₀BF₂NNaO₄ (M+Na)⁺: m/z=432.2; found: 432.2.

Step 3.5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(28.5 mg, 0.068 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 8.0 mg, 10.17 μmol) and cesium carbonate (66.8 mg, 0.205mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(24.7 mg, 0.060 mmol) in 1,4-Dioxane (2.00 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 mins, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₄H24F₂N₇O (M+H)⁺:m/z=464.2; found: 464.2.

Example 118.5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,3-dihydro-1H-inden-1-amine

Step 1. tert-Butyl 5,7-difluoro-2,3-dihydro-1H-inden-1-ylcarbamate

To a solution of boc-anhydride (1.398 g, 6.41 mmol) in CH₂Cl₂ (15.0 ml)was added 5,7-difluoro-2,3-dihydro-1H-inden-1-amine. HCl salt (AstaTech,1.002 g, 4.87 mmol) followed by N,N-diisopropylethylamine (2.93 ml,16.78 mmol). The mixture was stirred at room temperature for 30 min, andthen concentrated. The residue was purified on silica gel (40 g, 0-100%EtOAc in hexanes) to give the desired product as a white solid (1.178 g,90%).

Step 2. tert-Butyl5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamate

To a solution of tert-butyl(5,7-difluoro-2,3-dihydro-1H-inden-1-yl)carbamate (1.168 g, 4.34 mmol)in THF (40.0 ml) at −78° C. under N₂ was added a solution of n-BuLi (2.5M in hexanes) (4.60 ml, 11.50 mmol) slowly via syringe over a period of20 mins. The reaction was allowed to warm to −60° C. and stirred for 60mins. The reaction was then cooled back to −78° C.2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.01 ml, 14.77mmol) was added slowly via syringe over a period of 20 mins. Afterstirring at −78° C. for 20 min, the reaction was allowed to warm to roomtemperature and stirred for 1 h. The reaction was quenched with sat.NaHCO₃, and extracted with Et₂O. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel (40 g, 0-100% EtOAc in hexanes) to give the desired productas a white foamy solid (893.5 mg, 52%). LCMS calculated forC₂₀H₂₈BF₂NNaO₄ (M+Na)⁺: m/z=418.2; found: 418.2.

Step 3.5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(28.5 mg, 0.068 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 8.0 mg, 10.17 μmol) and cesium carbonate (70.0 mg, 0.215mmol). The vial was sealed with a Teflon-lined septum, evacuated andbackfilled with nitrogen (this process was repeated a total of threetimes). A solution of tert-butyl(5,7-difluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate(24.9 mg, 0.063 mmol) in 1,4-dioxane (2.00 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 min, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₃H₂₂F₂N₇O (M+H)⁺:m/z=450.2; found: 450.3.

Example 119.5-Fluoro-7-methoxy-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine

Step 1. tert-Butyl 5-fluoro-7-methoxy-2,3-dihydro-1H-inden-1-ylcarbamate

To a mixture of 5-fluoro-7-methoxy-2,3-dihydro-1H-inden-1-one (NetChem,1742.0 mg, 9.67 mmol), sodium cyanotrihydroborate (6212.9 mg, 99 mmol)and ammonium acetate (18.12 g, 235 mmol) was added 2-propanol (60.0 ml).The reaction was stirred at 70° C. for 16 h. After cooling to roomtemperature, the mixture was diluted with 2 N NaOH(aq) and extractedwith CH₂Cl₂ (×10). The organic layer was dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was dissolved in CH₂Cl₂ (40 ml),and was treated with boc-anhydride (2.156 g, 9.88 mmol). After stirringat room temperature for 30 mins, the reaction was concentrated. Theresidue was purified on silica gel (120 g, 0-100% EtOAc in hexanes) togive the desired product as a white solid (1.886 g, 69%). LCMScalculated for C₁₁H₁₃FNO₃ (M+H—C₄H₈)⁺: m/z=226.1; found: 226.1.

Step 2. tert-Butyl5-fluoro-7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamate

To a solution of tert-butyl(5-fluoro-7-methoxy-2,3-dihydro-1H-inden-1-yl)carbamate (1.886 g, 6.70mmol) in THF (40.0 ml) at −78° C. under N₂ was added a solution ofn-BuLi (2.5 M in hexanes) (7.50 ml, 18.75 mmol) slowly via syringe overa period of 20 mins. The reaction was allowed to warm to −60° C. andstirred for 60 mins. The reaction was then cooled back to −78° C.2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.00 ml, 24.51mmol) was added slowly via syringe over a period of 20 mins. Afterstirring at −78° C. for 20 mins, the reaction was allowed to warm toroom temperature and stirred for 1 h. The reaction was quenched withsat. NaHCO₃, and extracted with Et₂O. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was purified onsilica gel (40 g, 0-50% EtOAc in hexanes) to give the desired product asa white foamy solid (1.063 g, 39%). LCMS calculated for C₂₁H₃₁BFNNaO₅(M+Na)⁺: m/z=430.2; found: 430.2.

Step 3.5-Fluoro-7-methoxy-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine

To a screw-cap vial equipped with a magnetic stir bar was addedtert-butyl5-chloro-3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(28.5 mg, 0.068 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-l,1 biphenyl)]palladium(II) (XPhos Pd G2, 8.0 mg, 10.17 μmol) and cesiumcarbonate (69.8 mg, 0.214 mmol). The vial was sealed with a Teflon-linedseptum, evacuated and backfilled with nitrogen (this process wasrepeated a total of three times). A solution of tert-butyl(5-fluoro-7-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate(25.8 mg, 0.063 mmol) in 1,4-dioxane (2.00 ml) was added via syringe,followed by water (200.0 μl). The reaction was heated to 50° C. for 16h. The reaction was concentrated. To the residue was added CH₂Cl₂ (2.0mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 min, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₄H₂₅FN₇O₂ (M+H)⁺:m/z=462.2; found: 462.1. ¹H NMR (TFA salt, 600 MHz, DMSO) δ 9.49 (s,1H), 9.17-9.14 (m, 1H), 8.44 (dd, J=9.0, 2.4 Hz, 1H), 8.15 (br, 3H),7.10 (d, J=8.9 Hz, 1H), 7.04 (d, J=9.0 Hz, 1H), 4.91 (m, 1H), 3.72-3.69(m, 4H), 3.55-3.51 (m, 4H), 3.46 (s, 3H), 3.17 (m, 1H), 3.01-2.89 (m,1H), 2.59-2.52 (m, 1H), 2.08 (m, 1H).

Example 120.6-Fluoro-N-methyl-5-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

Step 1. tert-Butyl5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate

To a solution of 5-bromo-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (ArkPharm, 312.6 mg, 1.286 mmol) in 2-propanol (10.0 ml) was addedmethylamine (2.0 M in methanol) (2.50 ml, 5.00 mmol) followed bytitanium(IV) isopropoxide (596.0 mg, 2.097 mmol). The mixture wasstirred at 35° C. for 16 h before it was cooled to room temperature.Sodium borohydride (53.4 mg, 1.412 mmol) was added. The reaction wasstirred at room temperature for 1 h, and was treated with HCl (1.0 N inwater) (30.0 ml, 30 mmol). The mixture was stirred at room temperaturefor 2 h, and was treated with NaOH (4.0 N in water) until the pH reached10. The mixture was extracted with Et₂O. The organic phase wasseparated, dried over anhydrous Na₂SO₄, filtered and concentrated. Theresidue was dissolved in CH₂Cl₂ (10 ml), and treated with boc-anhydride(426.4 mg, 1.954 mmol). After stirring at room temperature for 30 min,the reaction was concentrated. The residue was purified on silica gel(40 g, 0-100% EtOAc in hexanes) to give the desired product (461.0 mg,89%). LCMS calculated for C₁₂H₁₄BrFNO₂ (M+H—C₄H₈)⁺: m/z=302.0; found:302.1.

Step 2. tert-Butyl6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl(methyl)carbamate

A vial was charged with4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](517.4 mg,2.037 mmol), potassium acetate (416.8 mg, 4.25 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexedwith dichloromethane (1:1) (210.2 mg, 0.257 mmol). The vial was sealed,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). A solution of tert-butyl(5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate(461.0 mg, 1.287 mmol) in 1,4-dioxane (6.0 ml) was added, and themixture was heated at 100° C. for 16 h. After cooling to roomtemperature, the reaction mixture was diluted with CH₂Cl₂ and filtered.The filtrate was concentrated. The residue was purified on silica gel(40 g, 0-100% EtOAc in hexanes) to give the desired product (337.4 mg,65%). LCMS calculated for C₂₂H₃₃BFNNaO₄ (M+Na)⁺ m/z=428.2; found 428.2.

Step 3.6-Fluoro-N-methyl-5-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

A vial was charged with tert-butyl5-chloro-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(34.0 mg, 0.079 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 8.0 mg, 10.17 μmol) and cesium carbonate (81.4 mg, 0.250mmol). The vial was sealed, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of tert-butyl(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)(methyl)carbamate(28.1 mg, 0.069 mmol) in 1,4-dioxane (2.0 ml) was added, followed bywater (200.0 μl). The reaction mixture was heated to 50° C. for 16 h.,cooled and concentrated. To the residue was added CH₂Cl₂ (2.0 mL)followed by TFA (2.0 mL). The mixture was stirred at room temperaturefor 15 mins, and then concentrated. The residue was purified usingprep-LCMS (XBridge C₁₋₈ column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated C₂₆H₃₀FN₈ (M+H)⁺: m/z=473.3;found: 473.3.

Example 121.6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

Step 1. tert-Butyl5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate

To a mixture of 5-bromo-6-fluoro-3,4-dihydronaphthalen-1(2H)-one (ArkPharm, 309.5 mg, 1.273 mmol), sodium cyanoborohydride (824.0 mg, 13.11mmol) and ammonium acetate (2.184 g, 28.3 mmol) was added 2-propanol(10.0 ml). The reaction was stirred at 70° C. for 16 h. After cooling toroom temperature, the mixture was diluted with 2 M K₂CO₃ (aq) andextracted with Et₂O. The organic phase was separated, was dried overanhydrous Na₂SO₄, filtered and concentrated. The residue was dissolvedin CH₂Cl₂ (20 ml), and was treated with Boc-anhydride (425.9 mg, 1.951mmol). After stirring at room temperature for 30 min, the reactionmixture was concentrated. The residue was purified on silica gel (40 g,0-100% EtOAc in hexanes) to give the desired product as a white solid(316.3 mg, 72%). LCMS calculated for C₁₁H₁₂BrFNO₂ (M+H—C₄H₈)⁺:m/z=288.0; found: 288.0.

Step 2. tert-Butyl6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate

A vial was charged with4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (319.0mg, 1.256 mmol), potassium acetate (272.1 mg, 2.77 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexedwith dichloromethane (1:1) (150.1 mg, 0.184 mmol). The vial was sealed,evacuated and backfilled with nitrogen (this process was repeated atotal of three times). A solution of tot-butyl(5-bromo-6-fluoro-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (316.3 mg,0.919 mmol) in 1,4-dioxane (6.0 ml) was added. The mixture was heated at100° C. for 16 h. After cooling to room temperature, the reactionmixture was diluted with CH₂Cl₂ and filtered. The filtrate wasconcentrated. The residue was purified on silica gel (40 g, 0-100% EtOAcin hexanes) to give the desired product (200.0 mg, 56%). LCMS calculatedfor C₁₇H₂₄BFNO₄ (M+H—C₄H₈)⁺: m/z=336.2; found: 336.3.

Step 3.6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine

A vial was charged with tert-butyl5-chloro-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine-1-carboxylate(30.0 mg, 0.070 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(XPhos Pd G2, 8.0 mg, 10.17 μmol) and cesium carbonate (72.8 mg, 0.223mmol). The vial was sealed, evacuated and backfilled with nitrogen (thisprocess was repeated a total of three times). A solution of tert-butyl(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate(25.0 mg, 0.064 mmol) in 1,4-dioxane (2.00 ml) was added, followed bywater (200.0 μl). The reaction was heated to 50° C. for 16 h. Thereaction was cooled and concentrated. To the residue was added CH₂Cl₂(2.0 mL) followed by TFA (2.0 mL). The mixture was stirred at roomtemperature for 15 min, and then concentrated. The residue was purifiedusing prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LCMS calculated for C₂₆H29FN₇ (M+H)⁺:m/z=458.3; found: 458.3.

Example 122.1-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)-4-methylpiperidin-4-ol

This compound was prepared according to the procedure described inExample 70, using 4-methylpiperidin-4-ol instead of2-methyl-1-(piperazin-1-yl)propan-2-ol as starting material. LC-MScalculated for C₂₄H26F₂N₇O (M+H)⁺: m/z=466.2; Found 466.2.

Example 123.1-(3,5-Difluoro-4-(3-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedure described inExample 72, using 1-(2-methoxyethyl)piperazine instead of1-(methylsulfonyl)piperidin-4-amine as starting material. LC-MScalculated for C₂₆H₃₀F₂N₇O (M+H)⁺: m/z=494.2; Found 494.2.

Example 124.1-(4-(3-(4-(4-Ethylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)-3-fluoro-5-(trifluoromethyl)phenyl)-N-methylmethanamine

This compound was prepared according to the procedure described inExample 76, using1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazineinstead of (6-(piperidin-1-yl)pyridin-3-yl)boronic acid as startingmaterial. LC-MS calculated for C₂₆H₂₈F₄N₇ (M+H)⁺: m/z=514.2; Found514.2. ¹H NMR (500 MHz, DMSO) δ 9.50 (s, 1H), 9.27 (bs, 1H), 8.30 (d,J=8.9 Hz, 2H), 7.97 (s, 1H), 7.90 (dd, 0.7=9.7, 1.6 Hz, 1H), 7.19-7.14(m, 2H), 4.38 (s, 2H), 4.02-3.90 (m, 2H), 3.59 (d, J=10.3 Hz, 2H),3.26-3.17 (q, J=7.3 Hz, 2H), 3.17-3.10 (d, J=20.8 Hz, 2H), 3.08 (s, 2H),2.69 (s, 3H), 1.27 (t, J=12 Hz, 3H).

Example 125.3-(4-(4-Ethylpiperazin-1-yl)phenyl)-5-(2-fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-1H-pyrazolo[4,3d]pyrimidine

This compound was prepared according to the procedures described inExample 81, using1-ethyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine,instead of1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazineas starting material. LCMS calculated for C₂₉H₃₅FN₇ (M+H)⁺: m/z=500.3;Found: 500.3.

Example 126.(R)-1-(3-Fluoro-4-(3-(6-(2-(methoxymethyl)morpholino)pyridin-3-yl)-1H-pyrazolo[4,3d]pyrimidin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine

Step 1.5-Chloro-3-(6-fluoropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine

To a solution of5-chloro-3-iodo-1-((2-(trimethylsilyl)ethoy)methyl)-1H-pyrazolo[4,3-d]pyrimidine(Example 1, step 2. 2.60 g, 6.33 mmol) in dioxane (24 ml) and water (6ml) were added potassium phosphate, tribasic (2.60 g, 12.7 mmol) and(6-fluoropyridin-3-yl)boronic acid (981 mg, 6.96 mmol). Nitrogen gas wasbubbled through the reaction mixture for 10 minutes and PdCl₂(dppf) (517mg, 0.633 mmol) was added. The reaction mixture was stirred at 90° C.for 2 hours. After cooling to r.t. it was concentrated to dryness. Theresidue was purified by silica gel chromatography using 0-100% ethylacetate in hexanes to afford desired product as brownish oil. LC-MScalculated for C₁₆H₂₀ClFN₅OSi (M+H)⁺: m/z=380.2; found 380.2.

Step 2. tert-Butyl3-fluoro-4-(3-(6-fluoropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)benzyl(methyl)carbamate

To a solution of tert-butyl(3-fluoro-5-(trifluoromethyl)benzyl)(methyl)carbamate (Step 1, example76, 4.50 g, 14.6 mmol) in THF (45.8 ml) was added 2.5M solution ofn-butyllithium in hexane (7.03 ml, 17.6 mmol) dropwise at −78° C. over60 mins. The resulting solution was stirred at −78° C. for 30 minsbefore 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.48 ml,22.0 mmol) was added. The reaction mixture was stirred for another 1hour, allowing it to warm up to r.t. It was acidified to pH=5 by 1N HClsolution. The resulting solution was diluted with ethyl acetate andwashed with water and brine. The organic layer was dried over MgSO₄,filtered and concentrated to dryness. The residue was dissolved indioxane (20 ml) and water (4 ml) and5-chloro-3-(6-fluoropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidine(1.39 g, 3.66 mmol) was added followed by potassium phosphate, tribasic(6.22 g, 29.3 mmol). Nitrogen gas was bubbled through the reactionmixture for 10 minutes.Chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (Xphos-Pd-G2, 0.691 g, 0.879 mmol) was added and thereaction mixture was stirred at 60° C. for 1 hour. After cooling tor.t., the reaction mixture was diluted with ethyl acetate and washedwith water and brine. The organic layer was dried over MgSO₄, filteredand concentrated to dryness. The residue was purified by silica gelchromatography using 0-100% ethyl acetate in hexanes to afford thedesired product as light yellowish oil. LC-MS calculated forC₃₀H₃₆F₅N₆O₃Si (M+H)⁺: m/z=651.2; found 651.2.

Step 3.(R)-1-(3-Fluoro-4-(3-(6-(2-(methoxymethyl)morpholino)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine

To a solution of tert-butyl3-fluoro-4-(3-(6-fluoropyridin-3-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)benzyl(methyl)carbamate(15 mg, 0.024 mmol) in DMSO (1 ml) was added(R)-2-(methoxymethyl)morpholine (31.7 mg, 0.242 mmol) followed by DIPEA(0.021 mL, 0.121 mmol). The resulting mixture was stirred at 120° C. for15 hours. The reaction mixture was then cooled to r.t., diluted with DCMand washed with water and brine. 1 mL of TFA was added to the separatedorganic phase and the resulting solution was stirred at 40° C. for 2hours. It was concentrated to dryness, diluted with methanol andpurified using prep-LCMS (XBridge C18 column, eluting with a gradient ofacetonitrile/water containing 0.1% TFA, at flow rate of 60 mL/min) toafford the desired product. LC-MS calculated for C₂₅H₂₆F₄N₇O₂ (M+H)⁺:m/z=532.2; found 532.2.

Example A. HPK1 Kinase Binding Assay

A stock solution of 1 mM test compound was prepared in DMSO. Thecompound plate was prepared by 3-fold and 11-point serial dilutions. 0.1μL of the compound in DMSO was transferred from the compound plate tothe white 384 well polystyrene plates. The assay buffer contained 50 mMHEPES, pH 7.5, 0.01% Tween-20, 5 mM MgCl₂, 0.01% BSA, and 5 mM DTT. 5 μlof 4 nM active HPK1 (SignalChem M23-11G) prepared in the buffer wasadded to the plate. The enzyme concentration given was based on thegiven stock concentration reported by the vender. 5 μl of 18 nM tracer222 (ThermoFisher PV6121) and 4 nM LanthaScreen Eu-Anti GST antibody(ThermoFisher PV5595) were added. After one hour incubation at 25° C.,the plates were read on a PHERAstar FS plate reader (BMG Labtech). Kivalues were determined.

Compounds of the present disclosure, as exemplified in Examples, showedthe K_(i) values in the following ranges: +=Ki≤100 nM; ++=100 nM<Ki≤500nM; +++=500 nM<Ki≤5000 nM.

TABLE 1 Example HPK1 Ki, nM 1 + 2 + 3 + 4 + 5 + 6 + 7 + 8 + 9 + 10 +11 + 12 + 13 ++ 14 + 15 + 16 ++ 17 + 18 ++ 19 + 20 +++ 21 + 22 ++ 23 +24 + 25 + 26 + 27 + 28 ++ 29 + 30 + 31 + 32 + 33 ++ 34 + 35 + 36 + 37 +38 + 39 + 40 + 41 + 42 + 43 + 44 + 45 + 46 + 47 ++ 48 + 49 + 50 + 51 +52 + 53 + 54 + 55 + 56 + 57 + 58 + 59 + 60 + 61 + 62 + 63 + 64 + 65 +66 + 67 + 68 + 69 + 70 + 71 + 72 + 73 + 74 + 75 + 76 + 77 + 78 + 79 +80 + 81 + 82 + 83 + 84 + 85 + 86 + 87 + 88 + 89 + 90 + 91 + 92 + 93 +94 + 95 + 96 + 97 + 98 + 99 + 100 + 101 + 102 + 103 + 104 + 105 + 106 +107 + 108 + 109 + 110 + 111 + 112 + 113 + 114 + 115 + 116 + 117 + 118 +119 + 120 + 121 + 122 + 123 + 124 + 125 + 126 +

Example B. p-SLP76S376 HTRF Assay

One or more compounds of the invention can be tested using thep-SLP76S376 HTRF assay described as follows. Jurkat cells (cultured inRPMI1640 media with 10% FBS) are collected and centrifuged, followed byresuspension in appropriate media at 3×10⁶ cells/ml. The Jurkat cells(35 ul) are dispensed into each well in a 384 well plate. Test compoundsare diluted with cell culture media for 40-fold dilution (adding 39 ulcell culture media into 1 ul compound). The Jurkat cells in the wellplate are treated with the test compounds at various concentrations(adding 5 ul diluted compound into 35 ul Jurkat cells and starting from3 uM with 1:3 dilution) for 1 hour at 37° C., 5% CO₂), followed bytreatment with anti-CD3 (5 ug/ml, OKT3 clone) for 30 min. A 1:25dilution of 100× blocking reagent (from p-SLP76 ser376HTRF kit) with 4×Lysis Buffer (LB) is prepared and 15 ul of the 4×LB buffer with blockingreagent is added into each well and incubated at room temperature for 45mins with gentle shaking. The cell lysate (16 ul) is added into aGreiner white plate, treated with p-SLP76 ser376HTRF reagents (2 uldonor, 2 ul acceptor) and incubated at 4° C. for overnight. Thehomogeneous time resolved fluorescence (HTRF) is measured on a PHERAstarplate reader the next day. IC₅₀ determination is performed by fittingthe curve of percent inhibition versus the log of the inhibitorconcentration using the GraphPad Prism 5.0 software.

Example C. Isolation of CD4+ or CD8+ T Cells and Cytokine Measurement

Blood samples are collected from healthy donors. CD4+ or CD8+ T cellsare isolated by negative selection using CD4+ or CD8+ enrichment kits(lifetech, USA). The purity of the isolated CD4+ or CD8+ T cells isdetermined by flow cytometry and is routinely >80%. Cells are culturedin RPMI 1640 supplemented with 10% FCS, glutamine and antibiotics(Invitrogen Life Technologies, USA). For cytokine measurement, Jurkatcells or primary CD4+ or CD8+ T cells are plated at 200 k cells/well andare stimulated for 24 h with anti-CD3/anti-CD28 beads in the presence orabsence of testing compounds at various concentrations. 16 μL ofsupernatants are then transferred to a white detection plate andanalyzed using the human IL2 or IFNγ assay kits (Cisbio).

Example D. Treg Assay

One or more compounds can be tested using the Regulatory T-cellproliferation assay described as following. Primary CD4+/CD25− T-cellsand CD4+/CD25+ regulatory T-cells are isolated from human donatedPeripheral Blood Mononuclear Cells, using an isolated kit from ThermoFisher Scientific (11363D). CD4+/CD25− T-cells are labeled with CFSE(Thermo Fisher Scientific, C34554) following the protocol provided bythe vendor. CFSE labeled T-cells and CD4+/CD25+ regulatory T-cells arere-suspended at the concentration of 1×106 cells/ml in RPMI-1640 medium.100 μl of CFSE-labeled T-cells are mixed with or without 50 μl ofCD4+/CD25+ regulatory T-cells, treated with 5 μl of anti-CD3/CD28 beads(Thermo Fisher Scientific, 11132D) and various concentrations ofcompounds diluted in 50 μl of RPMI-1640 medium. Mixed populations ofcells are cultured for 5 days (37° C., 5% CO₂) and proliferation ofCFSE-labeled T-cells is analyzed by BD LSRFortessa X-20 using FITCchannel on the 5th day.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

1-57. (canceled)
 58. A method for treating a cancer in a patient, saidmethod comprising: administering to the patient a therapeuticallyeffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt thereof wherein: R¹ is selectedfrom Cy¹, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, halo, CN, OR^(a),SR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)OR^(a), NR^(c)S(O)R^(b),NR^(c)S(O)₂R^(b), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b), andS(O)₂NR^(c)R^(d); wherein said C₂₋₆ alkenyl and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰; Cy¹ is selected from C₃₋₁₀cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the4-10 membered heterocycloalkyl and 5-10 membered heteroaryl each has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein a ring-forming carbon atom of 5-10membered heteroaryl and 4-10 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 memberedheteroaryl are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁰; Cy^(A) is selected fromC₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the 5-10 memberedheteroaryl has at least one ring-forming carbon atom and 1, 2, 3, or 4ring-forming heteroatoms independently selected from N, O, and S;wherein the N and S are optionally oxidized; wherein a ring-formingcarbon atom of the 5-10 membered heteroaryl is optionally substituted byoxo to form a carbonyl group; and wherein the C₆₋₁₀ aryl and 5-10membered heteroaryl are each optionally substituted with 1, 2, 3, 4 or 5substituents independently selected from R²⁰; each R¹⁰ is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1),NR^(c1)C(O)NR^(c1)R^(d1), C(═NR^(e1))R^(b1), C(═NOR^(a1))R^(b1),C(═NR^(e1))NR^(c1)R^(d1), NR^(c1)C(═NR^(e1))NR^(c1)R^(d1),NR^(c1)S(O)R^(b1), NR^(c1)S(O)R^(b1), NR^(c1)S(O)NR^(c1)R^(d1),S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), and S(O)₂NR^(c1)R^(d1);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹¹; or two R¹⁰ substituents taken togetherwith the carbon atom to which they are attached form a spiro3-7-membered heterocycloalkyl ring, or a spiro C₃₋₆ cycloalkyl ring;wherein each spiro 3-7-membered heterocycloalkyl ring has at least onering-forming carbon atom and 1, 2 or 3, ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each spiro 3-7-membered heterocycloalkyl ring is optionallysubstituted by oxo to form a carbonyl group; and wherein the spiro3-7-membered heterocycloalkyl ring and spiro C₃₋₆ cycloalkyl ring areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹¹; each R¹¹ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, OR^(a3), SR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3), C(O)OR^(a3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)C(O)OR^(a3), NR^(c3)S(O)R^(b3),NR^(c3)S(O)₂R^(b3), NR^(c3)S(O)₂NR^(c3)R^(d3), S(O)R^(b3),S(O)NR^(c3)R^(d3), S(O)₂R^(b3), and S(O)₂NR^(c3)R^(d3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃ alkylene areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²; each R¹² is independently selected fromC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-7 membered heterocycloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),NR^(c5)R^(d5), NR^(c5)C(O)R^(b5), NR^(c5)C(O)OR^(a5), NR^(c5)S(O)R^(b5),NR^(c5)S(O)₂R^(b5), NR^(c5)S(O)₂NR^(c5)R^(d5), S(O)R^(b5),S(O)NR^(c5)R^(d5), S(O)₂R^(b5), and S(O)₂NR^(c5)R^(d5); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl and 4-7 membered heterocycloalkyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R^(g); each R²⁰ is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃ alkylene,C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃ alkylene, halo,CN, NO₂, OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),OC(O)R^(b2), OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)C(O)NR^(c2)R^(d2), C(═NR^(e2))R^(b2),C(═NOR^(a2))R^(b2), C(═NR^(e2))NR^(c2)R^(d2),NR^(c2)C(═NR^(e2))NR^(c2)R^(d2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2),NR^(c2)S(O)₂NR^(c2)R^(d2), S(O)R^(b2), S(O)NR^(c2)R^(d2), S(O)₂R^(b2),and S(O)₂NR^(c2)R^(d2); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²¹; or twoadjacent R²⁰ substituents on the Cy^(A) ring, taken together with theatoms to which they are attached, form a fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring; wherein thefused 4-, 5-, 6- or 7-membered heterocycloalkyl ring each has at leastone ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatomsindependently selected from N, O, and S; wherein a ring-forming carbonatom of each fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring isoptionally substituted by oxo to form a carbonyl group; and wherein thefused 4-, 5-, 6- or 7-membered heterocycloalkyl ring and fused C₃₋₇cycloalkyl ring are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²¹; each R²¹ is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 memberedheteroaryl-C₁₋₃ alkylene, halo, CN, OR^(a4), SR^(a4), C(O)R^(b4),C(O)NR^(c4)R^(d4), C(O)OR^(a4), NR^(c4)R^(d4), NR^(c4)C(O)R^(b4),NR^(c4)C(O)OR^(a4), NR^(c4)S(O)R^(b4), NR^(c4)S(O)₂R^(b4),NR^(c4)S(O)₂NR^(c4)R^(d4), S(O)R^(b4), S(O)NR^(c4)R^(d4), S(O)₂R^(b4),and S(O)₂NR^(c4)R^(d4); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R²²; or two R²¹substituents taken together with the carbon atom to which they areattached form a spiro 3-7-membered heterocycloalkyl ring, or a spiroC₃₋₆ cycloalkyl ring; wherein each spiro 3-7-membered heterocycloalkylring has at least one ring-forming carbon atom and 1, 2 or 3ring-forming heteroatoms independently selected from N, O, and S;wherein a ring-forming carbon atom of each spiro 3-7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the spiro 3-7-membered heterocycloalkyl ringand spiro C₃₋₆ cycloalkyl ring are each optionally substituted with 1,2, 3 or 4 substituents independently selected from R²²; each R²² isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 4-7membered heterocycloalkyl, halo, CN, OR^(a6), SR^(a6), C(O)R^(b6),C(O)NR^(c6)R^(d6), C(O)OR^(a6), NR^(c6)R^(d6), NR^(c6)C(O)R^(b6),NR^(c6)C(O)OR^(a6), NR^(c6)S(O)R^(b6), NR^(c6)S(O)₂R^(b6),NR^(c6)S(O)₂NR^(c6)R^(d6), S(O)R^(b6), S(O)NR^(c6)R^(d6), S(O)₂R^(b6),and S(O)₂NR^(c6)R^(d6); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); each R^(a), R^(c),and R^(d) is independently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹⁰; or any R^(c) and R^(d) attached to the same N atom,together with the N atom to which they are attached, form a 4-10membered heterocycloalkyl group optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁰; each R^(b) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl,and 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹⁰; each R^(a1),R^(c1) and R^(d1) is independently selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R¹¹; or any R^(c1) and R^(d1) attached to the same N atom,together with the N atom to which they are attached, form a 4-, 5-, 6-or 7-membered heterocycloalkyl group optionally substituted with 1, 2, 3or 4 substituents independently selected from R¹¹; each R^(b1) isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryland 5-10 membered heteroaryl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl and 5-10 membered heteroaryl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹; each R^(e1)is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl, di(C₁₋₆alkyl)carbamyl,aminosulfonyl, C₁₋₆ alkylaminosulfonyl and di(C₁₋₆ alkyl)aminosulfonyl;each R^(a2), R^(c2) and R^(d2) is independently selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl;wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroarylare each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²¹; or any R^(c2) and R^(d2) attached tothe same N atom, together with the N atom to which they are attached,form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹; each R^(b2) is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹; each R^(e2) is independently selected from H, CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkylthio, C₁₋₆alkylsulfonyl, C₁₋₆alkylcarbonyl, C₁₋₆ alkylaminosulfonyl, carbamyl, C₁₋₆ alkylcarbamyl,di(C₁₋₆alkyl)carbamyl, aminosulfonyl, C₁₋₆ alkylaminosulfonyl anddi(C₁₋₆ alkyl)aminosulfonyl; each R^(a3), R^(c3) and R^(d3) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R¹²; or any R^(c3) andR^(d3) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R¹²; each R^(b3) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹²; each R^(a4), R^(c4) and R^(d4) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl and 4-7membered heterocycloalkyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R²²; or any R^(c4) andR^(d4) attached to the same N atom, together with the N atom to whichthey are attached, form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2 or 3 substituents independentlyselected from R²²; each R^(b4) is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl;wherein said C₁₋₆ alkyl C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl,phenyl, 5-6 membered heteroaryl and 4-7 membered heterocycloalkyl areeach optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R²²; each R^(a5), R^(c5) and R^(d5) isindependently selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyland C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R^(g); each R^(b5) is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; whereinsaid C₁₋₆ alkyl C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R^(a6), R^(c6) and R^(d6) is independently selected from H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ haloalkyl; wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR^(g); each R^(b6) is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, and C₁₋₆ haloalkyl; wherein said C₁₋₆ alkyl, C₂₋₆alkenyl and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g); and each R^(g) isindependently selected from OH, NO₂, CN, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₂alkylene, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, C₁₋₃ alkoxy-C₁₋₃ alkyl, C₁₋₃alkoxy-C₁₋₃ alkoxy, HO—C₁₋₃ alkoxy, HO—C₁₋₃ alkyl, cyano-C₁₋₃ alkyl,H₂N—C₁₋₃ alkyl, amino, C₁₋₆ alkylamino, di(C₁₋₆ alkyl)amino, thio, C₁₋₆alkylthio, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, carbamyl, C₁₋₆alkylcarbamyl, di(C₁₋₆ alkyl)carbamyl, carboxy, C₁₋₆ alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆ alkylcarbonylamino, C₁₋₆ alkylsulfonylamino,aminosulfonyl, C₁₋₆ alkylaminosulfonyl, di(C₁₋₆ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₆ alkylaminosulfonylamino, di(C₁₋₆alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₆alkylaminocarbonylamino, and di(C₁₋₆ alkyl)aminocarbonylamino; providedthat: 1) R¹ is other than NHC(O)CH₂CH₂CH₃; and 2) when Cy^(A) isunsubstituted or substituted pyrazol-4-yl, then R¹ is other thanpyridin-4-yl substituted by morpholine.
 59. The method of claim 58,wherein the cancer is selected from breast cancer, colorectal cancer,lung cancer, ovarian cancer, and pancreatic cancer.
 60. The method ofclaim 58, wherein R¹ is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ haloalkyl, halo, CN, OR^(a), SR^(a), C(O)R^(b), C(O)NR^(c)R^(d),C(O)OR^(a), and NR^(c)C(O)R^(b); wherein said C₂₋₆ alkenyl and C₂₋₆alkynyl are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹⁰.
 61. The method of claim 58, wherein R¹is selected from Cy¹, C₂₋₆ alkenyl, C₂₋₆ alkynyl and OR^(a); whereinsaid C₂₋₆ alkenyl and C₂₋₆ alkynyl are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹⁰.
 62. Themethod of claim 58, wherein R¹ is C₂₋₆ alkenyl; wherein said C₂₋₆alkenyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from R¹⁰.
 63. The method of claim 58, wherein R¹is CHCH substituted with R¹⁰, and R¹⁰ is phenyl substituted with4-methylpiperazin-1-yl.
 64. The method of claim 58, wherein R¹ is Cy¹.65. The method of claim 58, wherein Cy¹ is selected from 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl; wherein the4-10 membered heterocycloalkyl and 5-10 membered heteroaryl each has atleast one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein the N and Sare optionally oxidized; wherein a ring-forming carbon atom of 5-10membered heteroaryl and 4-10 membered heterocycloalkyl is optionallysubstituted by oxo to form a carbonyl group; and wherein the 4-10membered heterocycloalkyl, C₆₋₁₀ aryl and 5-10 membered heteroaryl areeach optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰.
 66. The method of claim 58, wherein Cy¹ is C₆₋₁₀ aryloptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R¹⁰.
 67. The method of claim 58, wherein Cy¹ is 5-10membered heteroaryl optionally substituted with 1, 2, 3 or 4substituents independently selected from R¹⁰.
 68. The method of claim58, wherein Cy¹ is phenyl, pyrazolyl, pyridinyl, pyrimidinyl,thiophenyl, and pyridone; wherein the phenyl, pyrazolyl, pyridinyl,pyrimidinyl, thiophenyl, or pyridone are each optionally substitutedwith 1, 2 or 3 substituents independently selected from R¹⁰.
 69. Themethod of claim 58, wherein each R¹⁰ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, NO₂, OR^(a1), SR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), C(O)OR^(a1), OC(O)R^(b1), OC(O)NR^(c1)R^(d1),NR^(c1)R^(d1), NR^(c1)C(O)R^(b1), NR^(c1)C(O)OR^(a1), NR^(c1)S(O)R^(b1),NR^(c1)S(O)₂R^(b1), S(O)R^(b1), S(O)NR^(c1)R^(d1), S(O)₂R^(b1), andS(O)₂NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10membered heteroaryl-C₁₋₃ alkylene are each optionally substituted with1, 2, 3, or 4 substituents independently selected from R¹¹.
 70. Themethod of claim 58, wherein each R¹⁰ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, OR^(a1), C(O)R^(b1), C(O)NR^(c1)R^(d1), C(O)OR^(a1),NR^(c1)R^(d1), and NR^(c1)C(O)R^(b1); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl,C₆₋₁₀ aryl, 5-10 membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene,4-10 membered heterocycloalkyl-C₁₋₃ alkylene, C₆₋₁₀ aryl-C₁₋₃ alkyleneand 5-10 membered heteroaryl-C₁₋₃ alkylene are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR¹¹.
 71. The method of claim 58, wherein each R¹⁰ is independentlyselected from C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl, 4-10 memberedheterocycloalkyl-C₁₋₃ alkylene, halo, CN, OR^(a1), C(O)R^(b1),C(O)NR^(c1)R^(d1), and NR^(c1)R^(d1); wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, and 4-10membered heterocycloalkyl-C₁₋₃ alkylene are each optionally substitutedwith 1, 2, or 3 substituents independently selected from R¹¹.
 72. Themethod of claim 58, wherein each R¹¹ is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene, 5-10 membered heteroaryl-C₁₋₃alkylene, halo, CN, OR^(a3), C(O)R^(b3), C(O)NR^(c3)R^(d3),NR^(c3)R^(d3), NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3), and S(O)₂R^(b3);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₃ alkylene, 4-10 membered heterocycloalkyl-C₁₋₃alkylene, C₆₋₁₀ aryl-C₁₋₃ alkylene and 5-10 membered heteroaryl-C₁₋₃alkylene are each optionally substituted with 1, 2, 3, or 4 substituentsindependently selected from R¹².
 73. The method of claim 58, whereineach R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, 4-10 membered heterocycloalkyl, halo, CN,OR^(a3), C(O)R^(b3), NR^(c3)R^(d3), C(O)NR^(c3)R^(d3),NR^(c3)C(O)R^(b3), NR^(c3)S(O)₂R^(b3), and S(O)₂R^(b3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, or3 substituents independently selected from R¹².
 74. The method of claim58, wherein each R¹¹ is independently selected from C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, 4-10 membered heterocycloalkyl,halo, CN, C(O)R^(b3), NR^(c3)R^(d3), and NR^(c3)C(O)R^(b3); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, Cv-m cycloalkyl, and 4-10membered heterocycloalkyl are each optionally substituted with 1, 2, or3 substituents independently selected from R¹².
 75. The method of claim58, wherein each R¹¹ is independently selected from C₁₋₆ alkyl, 4-10membered heterocycloalkyl, CN, C(O)R^(b3), and NR^(c3)R^(d3); whereinsaid C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are each optionallysubstituted with 1, 2, or 3 substituents independently selected fromR¹².
 76. The method of claim 58, wherein each R¹² is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,halo, CN, OR^(a5), SR^(a5), C(O)R^(b5), C(O)NR^(c5)R^(d5), C(O)OR^(a5),NR^(c5)R^(d5), or NR^(c5)C(O)R^(b5); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R^(g).
 77. The method ofclaim 58, wherein each R¹² is independently selected from C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo, and OR^(a5).
 78. Themethod of claim 58, wherein each R¹² is independently OR^(a5).
 79. Themethod of claim 58, wherein each R¹² is independently selected from C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.
 80. The method of claim 58,wherein each R¹² is C₁₋₆ alkyl.
 81. The method of claim 58, wherein R¹⁰is 4-methylpiperazin-1-yl, fluoro, methyl, CN, trifluormethyl, methoxy,N,N-dimethylaminocarbonyl, (4-methylpiperazin-1-yl)methyl,4-morpholinylmethyl, morpholinyl, piperazin-1-yl, pyrrolidin-1-yl,N,N-dimethylamine, morpholinylmethanone, N-cyclopentylaminocarbonyl,4-(cycloprop-1-yl)morpholine, cyanomethyl, 4-ethylpiperazin-1-yl,N-methylaminocarbonyl, cyclopropyl, pyridin-1-yl, methylamine,1-methyl-1-cyanomethyl, tetrahydro-2H-pyran-4-yl, phenyl,1-(piperazin-1-yl)ethan-1-one, 3-hydroxy-piperidin-1-yl,4-cyano-piperidin-1-yl, 3-hydroxy-pyrrolidin-1-yl, piperidin-4-yl,4-(2-methyl-2-hydroxypropyl)piperazin-1-yl,3-methyl-3(methylhydroxy)piperidin-1-yl,1-(methylsulfonyl)piperidin-4-amino, 4-(ethylhydroxy)piperazin-1-yl,4-(methylsulfonyl)piperazin-1-yl,4-((N-methyl-N-ethyl)aminocarbonyl)piperazin-1-yl, piperidin-1-yl,4-(methylcarbonyl)piperazin-1-yl, 2-cyanophenyl,1-hydroxyethane-2-amino, (methylsulfonyl)amino-methyl,azetidin-1-ylsulfonyl, difluoromethoxy, 2-(methoxymethyl)morpholin-4-yl,4-methyl-4-hydroxypiperidin-1-yl, or 4-(2-methoxyethyl)piperazin-1-yl.82. The method of claim 58, wherein R¹⁰ is 4-methylpiperazin-1-yl,fluoro, methyl, CN, trifluormethyl, methoxy, N,N-dimethylaminocarbonyl,(4-methylpiperazin-1-yl)methyl, 4-morpholinylmethyl, morpholinyl,piperazin-1-yl, pyrrolidin-1-yl, N,N-dimethylamine,morpholinylmethanone, N-cyclopentylaminocarbonyl,4-(cycloprop-1-yl)morpholine, cyanomethyl, 4-ethylpiperazin-1-yl,N-methylaminocarbonyl, cyclopropyl, pyridin-1-yl, methylamine,1-methyl-1-cyanomethyl, tetrahydro-2H-pyran-4-yl, phenyl, or1-(piperazin-1-yl)ethan-1-one.
 83. The method of claim 58, whereinCy^(A) is selected from C₆₋₁₀ aryl and 6-10 membered heteroaryl; whereinthe 6-10 membered heteroaryl has at least one ring-forming carbon atomand 1 or 2 ring-forming N heteroatoms; wherein a ring-forming carbonatom of the 6-10 membered heteroaryl is optionally substituted by oxo toform a carbonyl group; and wherein the C₆₋₁₀ aryl and 6-10 memberedheteroaryl are each optionally substituted with 1, 2, 3 or 4substituents independently selected from R²⁰.
 84. The method of claim58, wherein Cy^(A) is phenyl, pyridinyl, isoindolin-1-onyl, orquinolinyl; wherein the phenyl, pyridinyl, isoindolin-1-onyl, are eachoptionally substituted with 1, 2, 3 or 4 substituents independentlyselected from R²⁰.
 85. The method of claim 58, wherein each R²⁰ isindependently selected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, 4-10 membered heterocycloalkyl, halo, CN, OR^(a2), SR^(a2),C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2), OC(O)R^(b2),OC(O)NR^(c2)R^(d2), NR^(c2)R^(d2), NR^(c2)C(O)R^(b2),NR^(c2)C(O)OR^(a2), NR^(c2)S(O)R^(b2), NR^(c2)S(O)₂R^(b2), S(O)R^(b2),S(O)NR^(c2)R^(d2), S(O)₂R^(b2), and S(O)₂NR^(c2)R^(d2); wherein saidC₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are each optionallysubstituted with 1, 2, 3, or 4 substituents independently selected fromR²¹; or two adjacent R²⁰ substituents on the Cy^(A) ring, taken togetherwith the atoms to which they are attached, form a fused 4-, 5-, 6- or7-membered heterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring;wherein the fused 4-, 5-, 6- or 7-membered heterocycloalkyl ring eachhas at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-formingheteroatoms independently selected from N, O, and S; wherein aring-forming carbon atom of each fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring is optionally substituted by oxo to form acarbonyl group; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1, 2, 3 or 4 substituents independently selected fromR²¹.
 86. The method of claim 58, wherein each R²⁰ is independentlyselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl,4-10 membered heterocycloalkyl, halo, OR^(a2), SR^(a2), C(O)R^(b2),C(O)NR^(c2)R^(d2), C(O)OR^(a2), NR^(c2)R^(d2), and NR^(c2)C(O)R^(b2);wherein said C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl are eachoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from R²¹; or two adjacent R²⁰ substituents on the Cy^(A) ring,taken together with the atoms to which they are attached, form a fused4-, 5-, 6- or 7-membered heterocycloalkyl ring, or a fused C₃₋₇cycloalkyl ring; and wherein the fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring and fused C₃₋₆ cycloalkyl ring are each optionallysubstituted with 1 or 2 substituents independently selected from R²¹.87. The method of claim 58, wherein each R²⁰ is independently selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, halo,OR^(a2), SR^(a2), C(O)R^(b2), C(O)NR^(c2)R^(d2), C(O)OR^(a2),NR^(c2)R^(d2), and NR^(c2)C(O)R^(b2); wherein said C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl are each optionally substituted with 1, 2, 3,or 4 substituents independently selected from R²¹; or two adjacent R²⁰substituents on the Cy^(A) ring, taken together with the atoms to whichthey are attached, form a fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring, or a fused C₃₋₇ cycloalkyl ring.
 88. The methodof claim 58, wherein each R²⁰ is independently selected from C₁₋₆ alkyl,halo, OR^(a2), C(O)R^(b2), and C(O)NR^(c2)R^(d2); or two adjacent R²⁰substituents on the Cy^(A) ring, taken together with the atoms to whichthey are attached, form a fused 4-, 5-, 6- or 7-memberedheterocycloalkyl ring.
 89. The method of claim 58, wherein R²⁰ isfluoro, methyl, methoxy, chloro, (morpholino)methanone,N-methylaminocarbonyl, aminocarbonyl, (methylamino)methyl,trifluoromethyl, pyrrolidin-2-yl, piperidin-2-yl,((pyrrolidin-1-yl)methyl)carbonylamino,((N,N-dimethylamino)methyl)carbonylamino, 1-(methylamino)-ethyl,(ethylamino)methyl, cyanomethyl, N-methylamino, or amino; or twoadjacent R²⁰ substituents on the Cy^(A) ring, taken together with theatoms to which they are attached, form a fused piperidinyl ring.
 90. Themethod of claim 58, wherein R²⁰ is fluoro, methyl, methoxy, chloro,(morpholino)methanone, N-methylaminocarbonyl, or aminocarbonyl; or twoadjacent R²⁰ substituents on the Cy^(A) ring, taken together with theatoms to which they are attached, form a fused piperidinyl ring.
 91. Themethod of claim 58, wherein Cy^(A) is 2-fluoro-6-methoxyphenyl.
 92. Themethod of claim 58, wherein the compound has Formula (IIa1), Formula(IIa2), Formula (IIa3), Formula (IIa4) or Formula (IIa5):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or
 4. 93. The method of claim 58, wherein the compound has Formula(IIb1):

or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3,4 or
 5. 94. The method of claim 58, wherein the compound has Formula(IIc1), Formula (IIc2) or Formula (IIc3):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, 2, 3,or 4; and n is 0, 1, 2, 3, 4, or
 5. 95. The method of claim 58, whereinthe compound is selected from:5-(2-Fluorophenyl)-3-[4-(4-methylpiperazin-1-yl)phenyl]-1H-pyrazolo[4,3-d]pyrimidine,3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-o-tolyl-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Chloro-6-fluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine,3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine,3-(4-(4-Methylpiperazin-1-yl)phenyl)-5-(5-methylpyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine,6-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)isoindolin-1-one,(5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)pyridin-3-yl)(morpholino)methanone,N-Methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)nicotinamide,5-(3-(4-(4-Methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline,5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Fluoro-6-methoxyphenyl)-3-phenyl-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Fluoro-6-methoxyphenyl)-3-(2-fluorophenyl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Fluoro-6-methoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Fluoro-6-methoxyphenyl)-3-(pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Fluoro-6-methoxyphenyl)-3-(pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidine,4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)benzonitrile,5-(2-Fluoro-6-methoxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Fluoro-6-methoxyphenyl)-3-(3-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Fluoro-6-methoxyphenyl)-3-o-tolyl-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Fluoro-6-methoxyphenyl)-3-(thiophen-3-yl)-1H-pyrazolo[4,3-d]pyrimidine,4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N,N-dimethylbenzamide,5-(2-Fluoro-6-methoxyphenyl)-3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine,4-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)benzyl)morpholine5-(2-Fluoro-6-methoxyphenyl)-3-(3-((4methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine4-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)morpholine,5-(2-Fluoro-6-methoxyphenyl)-3-(3-(piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2-fluoro-6-methoxyphenyl)-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine,4-(3-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)morpholine,3-(5-(2-Fluoro-6-methoxyphenyl)-H-pyrazolo[4,3-d]pyrimidin-3-yl)-N,N-dimethylaniline,(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)(morpholino)methanone,N-Cyclopentyl-4-(5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)benzamide,4-(1-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)cyclopropyl)morpholine,2-(4-(5-(2-Fluoro-6-methoxyphenyl)-1lH-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)acetonitrile,5-(2-Fluoro-6-methoxyphenyl)-3-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Fluoro-6-methoxyphenyl)-3-(4-fluorophenyl)-1H-pyrazolo[4,3-d]pyrimidine,3-(4-(4-Ethylpiperazin-1-yl)phenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine,4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N-methylbenzamide,3-(4-Cyclopropylphenyl)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Fluoro-6-methoxyphenyl)-3-(4-(piperidin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine,(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)methanamine,2-(4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)-2-methylpropanenitrile,5-(2-Fluoro-6-methoxyphenyl)-3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2,3-Difluorophenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2,3-Difluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine,2-Fluoro-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzamide,2-Fluoro-N-methyl-3-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzamide,5-(2-Fluoro-6-methoxyphenyl)-3-(1-phenyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidine,4-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-1-methylpyridin-2(1H)-one,5-(2-Fluoro-6-methoxyphenyl)-3-(2-(piperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Fluoro-6-methoxyphenyl)-3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidine,5-(2-Fluoro-6-methoxyphenyl)-3-(6-(piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine,4-(5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)morpholine,1-(4-(5-(5-(2-Fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)piperazin-1-yl)ethan-1-one,(E)-5-(2-Fluoro-6-methoxyphenyl)-3-(4-(4-methylpiperazin-1-yl)styryl)-1H-pyrazolo[4,3-d]pyrimidine,and6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline,or a pharmaceutically acceptable salt thereof.
 96. The method of claim58, wherein the compound is selected from:1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)piperidin-3-ol;1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)piperidine-4-carbonitrile;5-(2-Fluoro-6-methylphenyl)-3-(4-(piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine;1-(4-(5-(2-Fluoro-6-methylphenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)pyrrolidin-3-ol;5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N-methylpicolinamide;4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-2-fluoro-N-methylbenzamide;1-(3,5-Difluoro-4-(3-(4-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;3-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)benzonitrile;1-(3,5-Difluoro-4-(3-(4-(piperidin-4-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;1-(3,5-Difluoro-4-(3-(4-(tetrahydro-2H-pyran-4-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;1-(4-(3-(4-(4-Ethylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3,5-difluorophenyl)-N-methylmethanamine;5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-2-morpholinonicotinonitrile;1-(3,5-Difluoro-4-(3-(3-fluoro-2-morpholinopyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;1-(4-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)piperazin-1-yl)-2-methylpropan-2-ol;(1-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)-3-methylpiperidin-3-yl)methanol;N-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)-1-(methylsulfonyl)piperidin-4-amine;2-(4-(4-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)piperazin-1-yl)ethanol;1-(3,5-Difluoro-4-(3-(6-(4-(methylsulfonyl)piperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;4-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)-N-ethyl-N-methylpiperazine-1-carboxamide;1-(3-Fluoro-4-(3-(6-(piperidin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine;1-(4-(5-(5-(2-Fluoro-4-((methylamino)methyl)-6-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)piperazin-1-yl)ethanone;1-(3-Fluoro-5-methyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;2-(4-(5-(2-Fluoro-6-methyl-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-1H-pyrazol-1-yl)benzonitrile;5-(2-Fluoro-6-methyl-4-(pyrrolidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine;5-(2-Fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine;N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-2-(pyrrolidin-1-yl)acetamide;N-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-2-(dimethylamino)acetamide;1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;1-(3,5-Difluoro-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylethanamine;1-(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;N-(3-Fluoro-5-methoxy-4-(3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)benzyl)ethanamine;5-(2-Fluoro-6-methoxyphenyl)-3-(3-methyl-1H-pyrazol-5-yl)-1H-pyrazolo[4,3-d]pyrimidine;3-(Benzyloxy)-5-(2-fluoro-6-methoxyphenyl)-1H-pyrazolo[4,3-d]pyrimidine;6,8-Difluoro-7-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;2-(5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyrimidin-2-ylamino)ethanol;6,8-Difluoro-7-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N,N-dimethylpyrimidin-2-amine;5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)-N-methylpyrimidin-2-amine;N-(4-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)benzyl)methanesulfonamide;7-(3-(4-(Azetidin-1-ylsulfonyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6,8-difluoro-1,2,3,4-tetrahydroisoquinoline;7-(3-(6-(Difluoromethoxy)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-6,8-difluoro-1,2,3,4-tetrahydroisoquinoline;4-(5-(5-(6,8-Difluoro-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)morpholine;6,8-Difluoro-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;8-Methoxy-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;8-Fluoro-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)quinoline;5-(4-Methoxypyridin-3-yl)-3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine;5-(4-Methoxypyridin-3-yl)-3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidine;N-Methyl-1-(4-methyl-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)pyridin-2-yl)methanamine;2-(3,5-Difluoro-4-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)acetonitrile;6-Fluoro-5-(3-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;6-Fluoro-8-methyl-7-(3-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;1-(4-(4-(5-(6-Fluoro-8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)phenyl)piperazin-1-yl)ethanone;4-(5-(5-(6-Fluoro-8-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)morpholine;6-Fluoro-8-methyl-7-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;6-Fluoro-8-methyl-7-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;8-Fluoro-6-methyl-7-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydroisoquinoline;4,6-Difluoro-N-methyl-5-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine;4,6-Difluoro-N-methyl-5-(3-(2-(4-methylpiperazin-1-yl)pyrimidin-5-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine;6,8-Difluoro-N-methyl-7-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-2-amine;5,7-Difluoro-N-methyl-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine;5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine;5,7-Difluoro-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine;5-Fluoro-7-methoxy-6-(3-(6-morpholinopyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-2,3-dihydro-1H-inden-1-amine;6-Fluoro-N-methyl-5-(3-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine;6-Fluoro-5-(3-(4-(4-methylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-1,2,3,4-tetrahydronaphthalen-1-amine;1-(5-(5-(2,6-Difluoro-4-((methylamino)methyl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-3-yl)pyridin-2-yl)-4-methylpiperidin-4-ol;1-(3,5-Difluoro-4-(3-(4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)phenyl)-N-methylmethanamine;1-(4-(3-(4-(4-Ethylpiperazin-1-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-3-fluoro-5-(trifluoromethyl)phenyl)-N-methylmethanamine;3-(4-(4-Ethylpiperazin-1-yl)phenyl)-5-(2-fluoro-6-methyl-4-(piperidin-2-yl)phenyl)-1H-pyrazolo[4,3-d]pyrimidine;and(R)-1-(3-Fluoro-4-(3-(6-(2-(methoxymethyl)morpholino)pyridin-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-5-(trifluoromethyl)phenyl)-N-methylmethanamine;or a pharmaceutically acceptable salt thereof.